Featured
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| Open AccessEpstein-Barr virus-driven B cell lymphoma mediated by a direct LMP1-TRAF6 complex
Epstein-Barr virus causes lymphoma. Here the authors describe a direct complex of the viral oncoprotein LMP1 with the cellular TRAF6 protein as a critical virus-host interface for lymphoma survival and validate this complex as a potential therapeutic target.
- Fabian Giehler
- , Michael S. Ostertag
- & Arnd Kieser
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Article
| Open AccessMcam inhibits macrophage-mediated development of mammary gland through non-canonical Wnt signaling
Mammary epithelial cells act to continuously renew the mammary tissue and must balance differentiation and self-renewal. Here they show that Mcam, a non-canonical Wnt pathway member, regulates communication between macrophages and mammary epithelial cells, thereby maintaining self-renewal and subsequently promoting mammary ductal morphogenesis.
- Xing Yang
- , Haibo Xu
- & Baowei Jiao
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Article
| Open AccessHijacking of internal calcium dynamics by intracellularly residing viral rhodopsins
Rhodopsins are ubiquitous light-driven membrane proteins that have diverse functions in nature, and value as optogenetics tools. Here the authors characterise type 1 viral channelrhodopsins, showing that they regulate intracellular calcium and can be used for the photocontrol of muscle contraction in vivo.
- Ana-Sofia Eria-Oliveira
- , Mathilde Folacci
- & Michel Vivaudou
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Article
| Open AccessInnate immune and proinflammatory signals activate the Hippo pathway via a Tak1-STRIPAK-Tao axis
The evolutionally conserved Hippo pathway regulates essential developmental, homeostatic and regenerative processes, and is involved in the host defense against pathogens. Here authors show that in Drosophila Melanogaster and mammalian cells, innate immune stimuli activate Hippo via a pathway emanating from the Tak1 kinase and cascading down to Hippo via STRIPAK-Tao-Hpo signaling.
- Yinan Yang
- , Huijing Zhou
- & Bo Liu
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Article
| Open AccessRedox-enabled electronic interrogation and feedback control of hierarchical and networked biological systems
With redox-linked synthetic biology and electrobiofabrication, electronic information can be transmitted in a bidirectional manner between biology and electronics. Here the authors design an electrogenetic platform that allows real time electronic control of biological functions from proteins and gene circuits to cell consortia.
- Sally Wang
- , Chen-Yu Chen
- & William E. Bentley
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Article
| Open AccessVWCE modulates amino acid-dependent mTOR signaling and coordinates with KICSTOR to recruit GATOR1 to the lysosomes
mTORC1 adapts cellular metabolism in response to nutrient signals. Here, the authors identify VWCE as a negative regulator of amino acid-dependent mTORC1 signaling and a potential as a therapeutic target in prostate cancer treatments.
- Tianyu Zhao
- , Yuanyuan Guan
- & Ying Liu
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Article
| Open AccessDissecting the genetic landscape of GPCR signaling through phenotypic profiling in C. elegans
To overcome challenges posted by vast number of GPCR genes and redundancy, the authors disrupted nearly all GPCR-encoding genes in C. elegans, enabling effective examination of GPCR signaling and offering a valuable resource for the research community.
- Longjun Pu
- , Jing Wang
- & Changchun Chen
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Article
| Open AccessThe function of ER-phagy receptors is regulated through phosphorylation-dependent ubiquitination pathways
Berkane et al. investigated the activation process of selective autophagy of the ER. They show that that phosphorylation of FAM134 proteins by CK2 is a prerequisite for the formation of large micro-clusters of high-density at the ER membrane.
- Rayene Berkane
- , Hung Ho-Xuan
- & Alexandra Stolz
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Article
| Open AccessRho GTPase activity crosstalk mediated by Arhgef11 and Arhgef12 coordinates cell protrusion-retraction cycles
Cell movements are achieved by the spatio-temporal coordination of local membrane protrusions and retractions. Here, the authors identify a mechanism by which these protrusion and retraction events are coupled and how this affects the directionality of cell movements.
- Suchet Nanda
- , Abram Calderon
- & Leif Dehmelt
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Article
| Open AccessCytoglobin regulates NO-dependent cilia motility and organ laterality during development
Developmental defects in left-right cardiac determination in humans are associated with ciliary dysfunction and low airway epithelial nitric oxide production. Here, the authors show that cytoglobin is essential for nitric oxide signaling, cilia function, and left-right patterning during zebrafish development.
- Elizabeth R. Rochon
- , Jianmin Xue
- & Paola Corti
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Article
| Open AccessStructures of human prostaglandin F2α receptor reveal the mechanism of ligand and G protein selectivity
Cryo-EM structures reveal the molecular mechanism of ligands and G protein selectivity for prostaglandin F2α receptor, providing guidance for development of better postpartum hemorrhage drugs.
- Xiuqing Lv
- , Kaixuan Gao
- & Xiangyu Liu
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Matters Arising
| Open AccessReply to: How carvedilol does not activate β2-adrenoceptors
- Evi Kostenis
- , Jesus Gomeza
- & Stefan Schulz
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Article
| Open AccessCurveCurator: a recalibrated F-statistic to assess, classify, and explore significance of dose–response curves
Dose-response curves are ubiquitous in pharmacology and biology, yet potency and effect size are often estimated even when there is no response. Here, authors present a statistical framework to assess curve significance and demonstrate how this aids drug mode of action analysis in large public datasets.
- Florian P. Bayer
- , Manuel Gander
- & Matthew The
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Article
| Open AccessA dynamic partitioning mechanism polarizes membrane protein distribution
Different membrane proteins dynamically polarize to organize signal transduction, but the underlying mechanism is unclear. Here, the authors show that a differential diffusion mediated partitioning process is sufficient to drive such spatiotemporal patterning of membrane-associated signaling proteins.
- Tatsat Banerjee
- , Satomi Matsuoka
- & Pablo A. Iglesias
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Article
| Open AccessNon-canonical pathway for Rb inactivation and external signaling coordinate cell-cycle entry without CDK4/6 activity
Cyclin-dependent kinases (CDK4/6) play a crucial role in initiating cell growth. Here, Zhang et al. unveil a mechanism that bypasses CDK4/6, shedding light on an alternative pathway of cell-cycle initiation and quiescence maintenance.
- Mimi Zhang
- , Sungsoo Kim
- & Hee Won Yang
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Article
| Open AccessEndosomal Arl4A attenuates EGFR degradation by binding to the ESCRT-II component VPS36
Endosomal EGFR signaling and lysosomal degradation play important roles in controlling numerous biological processes. Here, the authors show that Arl4A negatively regulates EGFR degradation by binding to VPS36 and attenuating ESCRT-mediated late endosomal EGFR sorting.
- Shin-Jin Lin
- , Ming-Chieh Lin
- & Fang-Jen S. Lee
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Article
| Open AccessNod1-dependent NF-kB activation initiates hematopoietic stem cell specification in response to small Rho GTPases
The signals that enable endothelial cells to switch to hemogenic to generate hematopoietic stem cells are poorly understood. Here, the authors identify an intracellular sensor of pathogens as an inductive developmental cue that primes this switch.
- Xiaoyi Cheng
- , Radwa Barakat
- & Raquel Espin-Palazon
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Article
| Open AccessStructures of the interleukin 11 signalling complex reveal gp130 dynamics and the inhibitory mechanism of a cytokine variant
Interleukin (IL-)11 is a signaling protein that plays key roles in several human diseases. Here the authors describe structures of IL-11 in complex with its receptors and determine the molecular mechanisms through which a variant of IL-11 inhibits signalling, opening avenues for therapeutic development.
- Riley D. Metcalfe
- , Eric Hanssen
- & Michael D. W. Griffin
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Article
| Open AccessTranscriptional responses of cancer cells to heat shock-inducing stimuli involve amplification of robust HSF1 binding
The authors compare the heat shock response between different cell lines and stimuli and reveal the genome-wide binding of its master transcription factor HSF1 as a platform for context-specific transcription activation.
- Sayantani Ghosh Dastidar
- , Bony De Kumar
- & Sergei Nechaev
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Article
| Open AccessHSP47 levels determine the degree of body adiposity
A complex interplay of various backgrounds and conditions determines the body fat levels of individuals. Here, the authors identify HSP47 as a pivotal determinant of body adiposity which is abundantly expressed in fat tissue and influenced by factors such as diet, exercise, hormones, and genetics.
- Jihoon Shin
- , Shinichiro Toyoda
- & Iichiro Shimomura
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Article
| Open AccessEncystation stimuli sensing is mediated by adenylate cyclase AC2-dependent cAMP signaling in Giardia
Giardia lamblia is an established model for studying encystation. Shih et al show bile and alkaline pH induce changes in membrane ordering, upregulate cAMP, and initiate encystation gene expression.
- Han-Wei Shih
- , Germain C. M. Alas
- & Alexander R. Paredez
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Article
| Open AccessDetermining zebrafish dorsal organizer size by a negative feedback loop between canonical/non-canonical Wnts and Tlr4/NFκB
Dorsal organizer initiates the dorsal-ventral axis formation in vertebrates. Here, the authors demonstrate that Tlr4/NFκB-mediated negative feedback regulation of Wnt/β-catenin signaling determines the precise size of the zebrafish dorsal organizer.
- Juqi Zou
- , Satoshi Anai
- & Tohru Ishitani
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Article
| Open AccessCell volume controlled by LRRC8A-formed volume-regulated anion channels fine-tunes T cell activation and function
During the activation and migration of T cells volume changes occur in response to osmolality cues which is not fully understood. Here the authors characterize the function of volume regulated ion channels in T cells and show that these channels regulate TCR sensitivity, thymic selection and TCR repertoire.
- Yuman Wang
- , Zaiqiao Sun
- & Ning Wu
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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 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 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 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 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 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 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 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 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 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 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 AccessAndrogen receptor is a determinant of melanoma targeted drug resistance
BRAF inhibitor response in melanoma is variable, and BRAF mutated patients often relapse. Here, the authors show that androgen receptor expression is linked to BRAF inhibitor response, and is a potential therapeutic target to increase efficacy.
- Anastasia Samarkina
- , Markus Kirolos Youssef
- & Gian Paolo Dotto
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Article
| Open AccessUSP36 stabilizes nucleolar Snail1 to promote ribosome biogenesis and cancer cell survival upon ribotoxic stress
Targeting ribosome biogenesis with the ribosome inhibitor, homoharringtonine (HHT), is effective in leukaemia but not in solid tumours. Here, the authors demonstrate that in solid tumours, activation of JNK signaling following HHT-induced ribosomal stress promotes Snail1 accumulation in the nucleolus which facilitates ribosome biogenesis and resistance to HHT.
- Kewei Qin
- , Shuhan Yu
- & Yong Yi
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Article
| Open AccessGLP-1R signaling neighborhoods associate with the susceptibility to adverse drug reactions of incretin mimetics
Agonists of the glucagon-like peptide-1 receptor are used to treat diabetes and obesity. Here, Wright et al. investigate the subcellular location of the receptor’s signaling events and uncover associations between signaling profiles and adverse drug reactions.
- Shane C. Wright
- , Aikaterini Motso
- & Volker M. Lauschke
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Article
| Open AccessLuminal Rank loss decreases cell fitness leading to basal cell bipotency in parous mammary glands
Rocha and co-authors show that loss of luminal Rank signaling causes abnormal alveolar differentiation and lactation failure. Subsequent pregnancies activate bipotency in basal cells, replacing unfit luminal cells, and restoring lactation.
- Ana Sofia Rocha
- , Alejandro Collado-Solé
- & Eva González-Suárez
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Article
| Open AccessThe USP46 deubiquitylase complex increases Wingless/Wnt signaling strength by stabilizing Arrow/LRP6
Wnt receptor levels drive signaling. Here the authors find that precise signaling in the Wnt morphogen gradient relies on Usp46, a deubiquitylase that enhances target cells sensitivity by increasing cell surface levels of the Wnt receptor Arrow/LRP6.
- Zachary T. Spencer
- , Victoria H. Ng
- & Yashi Ahmed
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Article
| Open AccessThe USP46 complex deubiquitylates LRP6 to promote Wnt/β-catenin signaling
Wnt receptors are controlled by their ubiquitin-mediated proteolysis. The authors show that the USP46 deubiquitylase complex potentiates Wnt signaling in human cells, Xenopus, and zebrafish by inhibiting cell surface LRP6 degradation.
- Victoria H. Ng
- , Zachary Spencer
- & Ethan Lee
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Article
| Open AccessCytoplasmic Endonuclease G promotes nonalcoholic fatty liver disease via mTORC2-AKT-ACLY and endoplasmic reticulum stress
Endonuclease G is known to translocate to the nucleus during apoptosis, but less is known about its role in the cytosol. Here, the authors show that cytoplasmic endonuclease G activates mTORC2 signaling and ER stress to promote NAFLD in female mice.
- Wenjun Wang
- , Junyang Tan
- & Qinghua Zhou
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Article
| Open AccessInterferon restores replication fork stability and cell viability in BRCA-defective cells via ISG15
Here the authors show that the basal activation of the interferon/ISG15 pathway is required for the stability of nascent DNA during replication and its upregulation promotes viability, proliferation and acquisition of drug resistance in BRCA1/2 deficient cells.
- Ramona N. Moro
- , Uddipta Biswas
- & Lorenza Penengo
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Article
| Open AccessFast, multiplexable and efficient somatic gene deletions in adult mouse skeletal muscle fibers using AAV-CRISPR/Cas9
Methods for somatic gene perturbation would offer advantages for screening multiple muscle gene candidates. Here the authors couple Cre-mediated skeletal muscle fiber-specific Cas9 expression with myotropic adeno-associated virus-mediated sgRNA delivery and report a system for effective somatic gene deletions in mice.
- Marco Thürkauf
- , Shuo Lin
- & Markus A. Rüegg
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Article
| Open AccessA common human MLKL polymorphism confers resistance to negative regulation by phosphorylation
MLKL is regarded as an executor of the necroptotic inflammatory cell death pathway. Here authors show, by introducing a mutation into mouse MLKL representing a frequently occurring human single nucleotide polymorphism, that MLKL mutations could critically alter the inflammatory response and the clearance of Salmonella from organs upon infection.
- Sarah E. Garnish
- , Katherine R. Martin
- & Joanne M. Hildebrand
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Article
| Open AccessThe TNFR Wengen regulates the FGF pathway by an unconventional mechanism
Mechanistic studies of receptor action have aided our understanding of developmental processes and facilitated drug development. Here they show that the TNFR-Wengen acts by forming a complex with the FGFR-Breathless, regulating its activity during cell differentiation in the developing respiratory system of Drosophila.
- Annalisa Letizia
- , Maria Lluisa Espinàs
- & Marta Llimargas
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Article
| Open AccessRegulation of cellular cholesterol distribution via non-vesicular lipid transport at ER-Golgi contact sites
The molecular mechanisms responsible for cellular cholesterol distribution remain unclear. Here, the authors identify a key role of lipid transfer proteins ORP9, OSBP, and GRAMD1s in maintaining cholesterol levels in the Golgi and plasma membrane.
- Tomoki Naito
- , Haoning Yang
- & Yasunori Saheki
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Article
| Open AccessFgf signalling triggers an intrinsic mesodermal timer that determines the duration of limb patterning
The limb bud is patterned by crosstalk between the mesoderm and the overlying apical ectodermal ridge, but it has been difficult to determine the requirement for different ligands in this process. Here the authors use a chick wing explant system to show that fibroblast growth factors trigger a mesodermal programme that is key for timing limb bud patterning.
- Sofia Sedas Perez
- , Caitlin McQueen
- & Matthew Towers
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Article
| Open AccessMechanodetection of neighbor plants elicits adaptive leaf movements through calcium dynamics
Pantazopoulou et al. discovered that leaves sense neighbors by mutual touching of hairs on their surface, called trichomes. Using fluorescent biosensors, they show that this triggers a calcium wave to activate leaf movement away from competitors
- Chrysoula K. Pantazopoulou
- , Sara Buti
- & Ronald Pierik