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Skp2–MacroH2A1–CDK8 axis orchestrates G2/M transition and tumorigenesis
Skp2 forms part of the SCF complex—an E3 ubiquitin ligase. Here the authors identify macroH2A1 as a novel target of Skp2 and propose an axis of regulation involving Skp2-macroH2A1-CDK8-p27 in cancer.
- Dazhi Xu
- , Chien-Feng Li
- & Hui-Kuan Lin
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The ancestral role of nodal signalling in breaking L/R symmetry in the vertebrate forebrain
The epithalamus exhibits left-right asymmetries with different magnitudes among vertebrates. Here, the authors show that the catshark and two lampreys have conserved molecular asymmetries between the left and right developing epithalamus which are controlled by nodal signalling.
- Ronan Lagadec
- , Laurent Laguerre
- & Agnès Boutet
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Microtubule disruption synergizes with oncolytic virotherapy by inhibiting interferon translation and potentiating bystander killing
Microtubule-destabilizing drugs and oncolytic viruses are two unrelated approaches to battle cancer. Here the authors show that microtubule-destabilizing drugs potentiate the efficiency of oncolytic rhabdoviruses by altering the cytokine production and response of the tumour cells.
- Rozanne Arulanandam
- , Cory Batenchuk
- & Jean-Simon Diallo
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The nuclear translocation of ERK1/2 as an anticancer target
The extracellular signal-regulated kinase 1/2 (ERK1/2) cascade is involved in the induction and maintenance of cancers. Here the authors design an ERK-derived peptide that blocks ERK nuclear import, thus proposing a novel approach to treat tumours with mutational activation of the ERK pathway.
- Alexander Plotnikov
- , Karen Flores
- & Rony Seger
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Suppressor of Deltex mediates Pez degradation and modulates Drosophila midgut homeostasis
The protein tyrosine phosphatase Pez controls intestinal stem cell proliferation in Drosophila by inhibiting the Hippo pathway transcription factor Yorkie. Wang et al. reveal that Pez protein stability is regulated by interactions with the E3 ubiquitin ligase Suppressor of Deltex.
- Chao Wang
- , Wenxiang Zhang
- & Lei Zhang
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| Open AccessMyeloid cell-derived inducible nitric oxide synthase suppresses M1 macrophage polarization
In response to microbial ligands, IRF5 promotes pro-inflammatory M1 macrophage activation and production of nitrous oxide. Here the authors show that nitrous oxide modifies IRF5 tyrosine residues as a negative feedback, limiting the inflammatory response and protecting from endotoxin shock.
- Geming Lu
- , Ruihua Zhang
- & Huabao Xiong
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| Open AccessLarge-scale determination of absolute phosphorylation stoichiometries in human cells by motif-targeting quantitative proteomics
Measuring phosphorylation stoichiometry on a proteomic scale remains a challenge. Tsai et al. develop a technique to measure the basal level of phosphorylation stoichiometry in a single human phosphoproteome and identify molecular changes associated with gefitinib resistance in lung cancer cells.
- Chia-Feng Tsai
- , Yi-Ting Wang
- & Yu-Ju Chen
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Attenuation of nonsense-mediated mRNA decay facilitates the response to chemotherapeutics
Nonsense-mediated mRNA decay (NMD) is a pathway that controls endogenous transcript levels and limits the production of aberrant mRNAs. Here the authors show that NMD is attenuated in cells treated with chemotherapeutic compounds through caspase-mediated proteolytic cleavage of UPF1, a key NMD effector.
- Maximilian W. Popp
- & Lynne E. Maquat
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EphrinB2 controls vessel pruning through STAT1-JNK3 signalling
Pruning of newly formed blood vessels is an important and yet poorly understood aspect of angiogenesis. Here the authors show that endothelial phosphotyrosine-dependent EphrinB2 signalling represses JNK3 function via STAT1, and identify JNK3 as an effector of endothelial cell death and vessel pruning in mice.
- Ombretta Salvucci
- , Hidetaka Ohnuki
- & Giovanna Tosato
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| Open AccessPD-1 alters T-cell metabolic reprogramming by inhibiting glycolysis and promoting lipolysis and fatty acid oxidation
Activation of T cells results in metabolic reprogramming to favour glycolysis. Here, Patsoukis et al. show that the surface receptor PD-1 inhibits glycolysis and increases the metabolism of lipids, providing a potential mechanism for the blockade of T effector functions but also for the longevity accompanying T cell exhaustion.
- Nikolaos Patsoukis
- , Kankana Bardhan
- & Vassiliki A. Boussiotis
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Interplay between glucose and leptin signalling determines the strength of GABAergic synapses at POMC neurons
Hypothalamic POMC neurons regulate organismal energy homeostasis. Here, Lee et al. show that leptin signalling and neurotransmitter release from POMC neurons are influenced by glucose concentrations, which may alter food intake and body weight in rodents before the onset of central leptin resistance.
- Dong Kun Lee
- , Jae Hoon Jeong
- & Young-Hwan Jo
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Orphan receptor IL-17RD regulates Toll-like receptor signalling via SEFIR/TIR interactions
Toll-like receptors detect conserved microbial features to initiate host defence and are tightly regulated. Here the authors show that the orphan receptor interleukin-17 receptor D negatively regulates signalling downstream of Toll-like receptors to prevent excessive inflammation.
- Mark Mellett
- , Paola Atzei
- & Paul N. Moynagh
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Fundamental origins and limits for scaling a maternal morphogen gradient
Maternal molecular resources are invested in an egg so that different parts of the future embryo are specified and scaled in proportion to its size. Here the authors develop and experimentally test a model that evaluates the origins and limits of Bicoid morphogenetic gradient scaling in the fruit fly embryo.
- Feng He
- , Chuanxian Wei
- & Jun Ma
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Generation and expansion of highly pure motor neuron progenitors from human pluripotent stem cells
Applications of human pluripotent stem cells (hPSCs) for disease modelling or cell therapy are hindered by low efficiency and heterogeneity of target cell types differentiated from hPSCs, such as motor neurons (MNs). Here the authors develop a method to derive highly pure motor neuron progenitor populations from human embryonic and induced pluripotent stem cells that yield functional MNs.
- Zhong-Wei Du
- , Hong Chen
- & Su-Chun Zhang
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A novel pathway producing dimethylsulphide in bacteria is widespread in soil environments
Dimethylsulphide (DMS) is a volatile compound produced by marine microbes through degradation of dimethylsulphoniopropionate (DMSP). Here, Carrión et al.describe an alternative pathway for DMS production from methanethiol that is widespread among bacteria, especially from soil environments.
- O. Carrión
- , A. R. J. Curson
- & J. D. Todd
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Muscarinic acetylcholine receptor M3 modulates odorant receptor activity via inhibition of β-arrestin-2 recruitment
Type three muscarinic acetylcholine receptors (M3-Rs) physically interact with olfactory receptors to potentiate odour-induced responses. Here, the authors demonstrate that acetylcholine potentiates odour-induced responses in olfactory sensory neurons via M3-R-mediated inhibition of β-arrestin-2 recruitment.
- Yue Jiang
- , Yun Rose Li
- & Hiroaki Matsunami
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| Open AccessXanthine oxidoreductase regulates macrophage IL1β secretion upon NLRP3 inflammasome activation
Activation of NLRP3 inflammasome requires generation of reactive oxygen species. Here the authors show that microbial or tissue damage-derived signals activate xanthine oxidase, which serves as a critical source of reactive oxygen species for inflammasome activation in macrophages.
- Annette Ives
- , Johji Nomura
- & Alexander So
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| Open AccessDissecting meiotic recombination based on tetrad analysis by single-microspore sequencing in maize
The crossovers and gene conversions that occur during meiotic recombination contribute to genome diversity in eukaryotes. Here Li et al. describe a method of isolating individual microspores for whole-genome sequencing, providing new insights into the generation of genome diversity through sexual reproduction.
- Xiang Li
- , Lin Li
- & Jianbing Yan
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| Open AccessAsymmetrically dividing Drosophila neuroblasts utilize two spatially and temporally independent cytokinesis pathways
In asymmetrically dividing cells, both spindle-dependent and spindle-independent cleavage furrow positioning pathways are involved in cytokinesis. Here the authors find that Survivin and the mitotic spindle are required to stabilize the position of the cleavage furrow and to complete cytokinesis in Drosophilaneuroblasts.
- Michaela Roth
- , Chantal Roubinet
- & Clemens Cabernard
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| Open AccessEnterohemorrhagic Escherichia coli senses low biotin status in the large intestine for colonization and infection
Enterohaemorrhagic Escherichia coli(EHEC) is an important foodborne pathogen that colonizes the large intestine. Here, the authors identify a signalling pathway that controls EHEC adherence to host cells in response to variations in biotin levels, ensuring selective colonization of the large intestine.
- Bin Yang
- , Lu Feng
- & Lei Wang
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Dietary methionine can sustain cytosolic redox homeostasis in the mouse liver
NADPH acts as a reducing currency in mammalian cells and is thought to be required to maintain redox homeostasis. Here the authors discover an alternative NADPH-independent pathway, based on the conversion of methionine into cysteine, which is capable of sustaining redox homeostasis in the mouse liver.
- Sofi Eriksson
- , Justin R. Prigge
- & Edward E. Schmidt
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| Open AccessThe intellectual disability protein RAB39B selectively regulates GluA2 trafficking to determine synaptic AMPAR composition
Mutations in the RAB39Bgene, which encodes a protein involved in vesicular trafficking, are associated with intellectual disability, but the impact of RAB39B loss of function on synaptic activity is not known. Here the authors show that RAB39B interacts with PICK1, and that this interaction is critical for the translocation of AMPA receptor subunits into the Golgi.
- Maria Lidia Mignogna
- , Maila Giannandrea
- & Patrizia D’Adamo
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| Open AccessRGS1 regulates myeloid cell accumulation in atherosclerosis and aortic aneurysm rupture through altered chemokine signalling
Vascular inflammation plays a key role in pathogenesis of major vascular diseases. Here the authors show that Regulator of G-Protein Signaling-1 (RGS1) controls macrophage function in the development of vascular inflammation that underlies atherosclerosis and abdominal aortic aneurysms in mice and humans.
- Jyoti Patel
- , Eileen McNeill
- & Keith M. Channon
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The class II PI 3-kinase, PI3KC2α, links platelet internal membrane structure to shear-dependent adhesive function
The lipid kinase PI3KC2α is essential for embryogenesis, yet its role in adult homeostasis is unknown. Here, the authors show that PI3KC2α regulates the structure of the internal membrane reserves of murine megakaryocytes and platelets, affecting the platelets’ adhesiveness and prothrombotic function.
- Jessica K. Mountford
- , Claire Petitjean
- & Shaun P. Jackson
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A RIPK2 inhibitor delays NOD signalling events yet prevents inflammatory cytokine production
Receptor Interacting Protein Kinase 2 (RIPK2) mediates innate immune signalling in response to intracellular pathogens, but its aberrant activation contributes to autoimmune pathologies. Here Nachbur et al.describe a RIPK2 inhibitor that is effective in a mouse model of multiple sclerosis.
- Ueli Nachbur
- , Che A. Stafford
- & John Silke
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IRF8 directs stress-induced autophagy in macrophages and promotes clearance of Listeria monocytogenes
Autophagy is critical for pathogen clearance by innate immune cells. Here the authors show that IRF8 is activated in response to autophagy-inducing stimuli, promotes autophagic progression by driving transcription of autophagy genes and is critical for clearance of intracellular bacteria.
- Monica Gupta
- , Dong-Mi Shin
- & Keiko Ozato
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ERK phosphorylation and miR-181a expression modulate activation of human memory TH17 cells
How the magnitude of the response is regulated in different T-cell memory subsets remains poorly understood. Here the authors show that miR-181 lowers the threshold of Th17 memory activation via sustained Erk phosphorylation, while Erk-dependent induction of ID3 limits Th17 activity at later time.
- Federico Mele
- , Camilla Basso
- & Silvia Monticelli
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Epsin is required for Dishevelled stability and Wnt signalling activation in colon cancer development
Wnt receptors and the cytoplasmic signalling adaptor, dishevelled (Dvl), are upregulated in cancer and result in elevated canonical Wnt signalling. Here the authors show that the adaptor protein Epsin acts as a chaperone that protects Dvl from degradation thereby contributing to excess Wnt signalling and colon cancer growth.
- Baojun Chang
- , Kandice L. Tessneer
- & Hong Chen
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HEB associates with PRC2 and SMAD2/3 to regulate developmental fates
In embryonic stem cells, extracellular signals are required to derepress developmental promoters to drive lineage specification, but the proteins involved in this process remain unknown. Here the authors show that the protein HEB directly associates with the Polycomb repressive complex 2 at genes involved in mesoderm and endoderm specification.
- Se-Jin Yoon
- , Joseph W. Foley
- & Julie C. Baker
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| Open AccessOriented cell division shapes carnivorous pitcher leaves of Sarracenia purpurea
The pitcher-shaped leaf of the carnivorous plant Sarracenia purpurea acts as a pitfall trap to capture small animals. Here, Fukushima et al. analyse pitcher leaf development and propose that this unusual shape evolved from ancestral planar leaves through changes in the orientation of cell division.
- Kenji Fukushima
- , Hironori Fujita
- & Mitsuyasu Hasebe
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Notch1–Dll4 signalling and mechanical force regulate leader cell formation during collective cell migration
Many forms of collective cell migration are directed by specialized leader cells that have a distinct protrusive phenotype. Riahi et al.show that lateral inhibition mediated by Notch1–Dll4 signalling determines the stochastic emergence of leader cells in epithelial monolayers.
- Reza Riahi
- , Jian Sun
- & Pak Kin Wong
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TOPBP1 recruits TOP2A to ultra-fine anaphase bridges to aid in their resolution
During chromosome segregation sister chromatids can be entangled, resulting in anaphase bridges that must be resolved. Here, the authors report that topoisomerase IIβ binding protein 1 recruits topoisomerase IIα to centromere-associated ultra-fine anaphase bridges to enable their efficient resolution.
- Ronan Broderick
- , Jadwiga Nieminuszczy
- & Wojciech Niedzwiedz
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| Open AccessMitochondrial SSBP1 protects cells from proteotoxic stresses by potentiating stress-induced HSF1 transcriptional activity
Heat shock induces proteotoxic stress, and the cellular response is mediated by heat-shock factor 1 (HSF1). Here, Tan et al.show that following heat shock, mitochondrial SSBP1 translocates to the nucleus and binds HSF1 to enhance the expression of chaperones and support the maintenance of mitochondrial function.
- Ke Tan
- , Mitsuaki Fujimoto
- & Akira Nakai
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Organelles maintain spindle position in plant meiosis
In many plants, male meiosis involves two rounds of chromosome separation without cell division, resulting in two spindles in a single cell. Here Brownfield et al. show that an organelle band acts as a physical barrier between the spindles to ensure accurate chromosome segregation.
- Lynette Brownfield
- , Jun Yi
- & Claudia Köhler
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Article
| Open AccessPlastid establishment did not require a chlamydial partner
Primary plastids descend from an endosymbiosis involving cyanobacteria, an ancient eukaryotic host and, possibly, a chlamydial pathogen. Here, Domman and colleagues use sophisticated phylogenetic methods to show that Chlamydiaedid not play a role in establishing the primary plastid endosymbiosis.
- Daryl Domman
- , Matthias Horn
- & Tom A. Williams
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Immunotoxin targeting glypican-3 regresses liver cancer via dual inhibition of Wnt signalling and protein synthesis
Tumour-targeted antibodies can kill cancer cells by blocking pro-survival signalling or by delivering a toxin. Here the authors show that glypican-3 antibody fused to a bacterial toxin suppresses tumour growth more efficiently if designed to block Wnt signalling downstream of glypican-3.
- Wei Gao
- , Zhewei Tang
- & Mitchell Ho
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Article
| Open AccessArtificial human Met agonists based on macrocycle scaffolds
Activation of the Met receptor by hepatocyte growth factor requires Met receptor dimerization. Here, the authors identify Met-binding peptide macrocycles that, in a dimeric form as a result of chemical crosslinking, induce Met receptor dimerization and activation in cultured human cells.
- Kenichiro Ito
- , Katsuya Sakai
- & Hiroaki Suga
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Integrin β1 controls VE-cadherin localization and blood vessel stability
The role of integrin β1 in angiogenesis is poorly understood. Here, the authors show that integrin β1 regulates murine angiogenesis and adherens junction integrity by controlling VE-cadherin localization, myosin light chain phosphorylation and the function of the Rap1/MRCK and Rho/Rho-kinase pathways.
- Hiroyuki Yamamoto
- , Manuel Ehling
- & Ralf H. Adams
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| Open AccessCenpj/CPAP regulates progenitor divisions and neuronal migration in the cerebral cortex downstream of Ascl1
The proneural factor Ascl1/Mash1 is an important regulator of embryonic neurogenesis. Here the authors identify that the microcephaly protein Cenpj/CPAP is essential for several microtubule-dependent steps in the neurogenic program driven by Ascl1 in the developing cerebral cortex.
- Patricia P. Garcez
- , Javier Diaz-Alonso
- & François Guillemot
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Article
| Open AccessDefective podocyte insulin signalling through p85-XBP1 promotes ATF6-dependent maladaptive ER-stress response in diabetic nephropathy
Diabetic kidney disease is associated with ER stress in podocytes. Here the authors use various genetically modified mouse models to study ER-stress-related signalling pathways and propose a mechanistic framework that links insulin signalling with ER stress in podocytes of diabetic mice.
- Thati Madhusudhan
- , Hongjie Wang
- & Berend Isermann
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Housing temperature-induced stress drives therapeutic resistance in murine tumour models through β2-adrenergic receptor activation
Anticancer treatments are tested in mice housed below thermoneutrality which represents chronic cold-stress. Here Eng et al. show that these mice have activated stress responses leading to therapeutic resistance and that inhibiting adrenergic signaling increases efficacy of anticancer therapies.
- Jason W.-L. Eng
- , Chelsey B. Reed
- & Bonnie L. Hylander
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Article
| Open AccessIdentification of FOXM1 as a therapeutic target in B-cell lineage acute lymphoblastic leukaemia
FOXM1, a transcription factor with roles in cell cycle progression, is highly expressed in the majority of solid tumours. Here the authors show that FOXM1 is an ideal therapeutic target in B-cell acute lymphoblastic leukaemia (ALL) due to its dispensability for normal B-cell development.
- Maike Buchner
- , Eugene Park
- & Markus Müschen
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Alendronate inhalation ameliorates elastase-induced pulmonary emphysema in mice by induction of apoptosis of alveolar macrophages
Macrophages have a role in the pathogenesis of pulmonary emphysema. Here the authors show that inhalation—but not oral delivery—of the anti-osteoporosis drug alendronate attenuates lung damage in a mouse model of emphysema by inducing apoptosis of alveolar macrophages.
- Manabu Ueno
- , Toshitaka Maeno
- & Masahiko Kurabayashi
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Use of the CRISPR/Cas9 system as an intracellular defense against HIV-1 infection in human cells
The CRISPR/Cas9 system can be used for genome editing. Here, Liao et al. show that the system can be adapted to inhibit HIV expression and replication, excise the integrated HIV genome and provide long-term protection against new infections in human cells, including pluripotent stem cells.
- Hsin-Kai Liao
- , Ying Gu
- & Juan Carlos Izpisua Belmonte
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Article
| Open AccessUpward synaptic scaling is dependent on neurotransmission rather than spiking
Synaptic upscaling is characterized by an increase in the strength of excitatory inputs to a neuron as a compensatory response to chronic reductions in spiking activity. Here, the authors demonstrate that reduced glutamatergic transmission, rather than reduced spiking activity, directly triggers upscaling.
- Ming-fai Fong
- , Jonathan P. Newman
- & Peter Wenner
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MtDNA mutagenesis impairs elimination of mitochondria during erythroid maturation leading to enhanced erythrocyte destruction
Accumulation of mitochondrial DNA (mtDNA) mutations is linked to severe anaemia by an unknown mechanism. Here the authors show that excessive mtDNA mutations impair mitochondrial expulsion during erythropoiesis leading to augmented erythrocyte clearance and anaemia in mice and humans.
- K.J. Ahlqvist
- , S. Leoncini
- & A. Suomalainen
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Chromokinesin Kid and kinetochore kinesin CENP-E differentially support chromosome congression without end-on attachment to microtubules
Alignment of chromosomes at the spindle equator involves two kinesin family molecular motors, Kid and CENP-E. Here, Iemura and Tanaka show differential contributions of these motors, whereby Kid promotes partial alignment before end-on microtubule attachment to chromosomes, and CENP-E promotes alignment when microtubules are stabilized.
- Kenji Iemura
- & Kozo Tanaka
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CCM-3/STRIPAK promotes seamless tube extension through endocytic recycling
Mutations in the CCM3 gene in humans lead to severe forms of cerebral cavernous malformation. Here, Lant et al. shed light on the mechanism of CCM-3 function in C. elegans, and show that CCM-3 ablation leads to defects in excretory canal extension and the formation of cysts reminiscent of human malformations.
- Benjamin Lant
- , Bin Yu
- & W Brent Derry
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Mitochondrial function and lifespan of mice with controlled ubiquinone biosynthesis
Ubiquinone is a redox-active molecule that is involved in mitochondrial electron transfer. Here, Wang et al. report a mouse model that allows for temporarily controlled ubiquinone synthesis, and show that shortened lifespan associated with lack of ubiquinone can be reversed if ubiquinone biosynthesis is restored.
- Ying Wang
- , Daniella Oxer
- & Siegfried Hekimi
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