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    Electron Cryo-microscopy Structure of Ebola Virus Nucleoprotein Reveals a Mechanism for Nucleocapsid-like Assembly.
    Cell 2018 Feb;172(5):966-978.e12
    Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA. Electronic address:
    Ebola virus nucleoprotein (eNP) assembles into higher-ordered structures that form the viral nucleocapsid (NC) and serve as the scaffold for viral RNA synthesis. However, molecular insights into the NC assembly process are lacking. Using a hybrid approach, we characterized the NC-like assembly of eNP, identified novel regulatory elements, and described how these elements impact function. Read More

    Inborn Errors of RNA Lariat Metabolism in Humans with Brainstem Viral Infection.
    Cell 2018 Feb;172(5):952-965.e18
    St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY 10065, USA; Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Paris 75015, France; Paris Descartes University, Imagine Institute, Paris 75015, France; Howard Hughes Medical Institute, New York, NY 10065, USA; Pediatric Immunology-Hematology Unit, Necker Hospital for Sick Children, Paris 75015, France.
    Viruses that are typically benign sometimes invade the brainstem in otherwise healthy children. We report bi-allelic DBR1 mutations in unrelated patients from different ethnicities, each of whom had brainstem infection due to herpes simplex virus 1 (HSV1), influenza virus, or norovirus. DBR1 encodes the only known RNA lariat debranching enzyme. Read More

    A Mild PUM1 Mutation Is Associated with Adult-Onset Ataxia, whereas Haploinsufficiency Causes Developmental Delay and Seizures.
    Cell 2018 Feb;172(5):924-936.e11
    Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Jan and Dan Duncan Neurological Research Institute at Texas Children's Hospital, Houston, TX 77030, USA; Howard Hughes Medical Institute, Baylor College of Medicine, Houston, TX 77030, USA; Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA; Program in Developmental Biology, Baylor College of Medicine, Houston, TX 77030, USA. Electronic address:
    Certain mutations can cause proteins to accumulate in neurons, leading to neurodegeneration. We recently showed, however, that upregulation of a wild-type protein, Ataxin1, caused by haploinsufficiency of its repressor, the RNA-binding protein Pumilio1 (PUM1), also causes neurodegeneration in mice. We therefore searched for human patients with PUM1 mutations. Read More

    Pervasive, Coordinated Protein-Level Changes Driven by Transcript Isoform Switching during Meiosis.
    Cell 2018 Feb;172(5):910-923.e16
    Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA 94720, USA. Electronic address:
    To better understand the gene regulatory mechanisms that program developmental processes, we carried out simultaneous genome-wide measurements of mRNA, translation, and protein through meiotic differentiation in budding yeast. Surprisingly, we observed that the levels of several hundred mRNAs are anti-correlated with their corresponding protein products. We show that rather than arising from canonical forms of gene regulatory control, the regulation of at least 380 such cases, or over 8% of all measured genes, involves temporally regulated switching between production of a canonical, translatable transcript and a 5' extended isoform that is not efficiently translated into protein. Read More

    Dissecting the Causal Mechanism of X-Linked Dystonia-Parkinsonism by Integrating Genome and Transcriptome Assembly.
    Cell 2018 Feb;172(5):897-909.e21
    Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA; Program in Medical and Population Genetics and Stanley Center for Psychiatric Research, Broad Institute, Cambridge, MA 02142, USA; The Collaborative Center for X-linked Dystonia-Parkinsonism, Massachusetts General Hospital, Charlestown, MA 02129, USA; Departments of Psychiatry and Pathology, Massachusetts General Hospital, Boston, MA 02114, USA. Electronic address:
    X-linked Dystonia-Parkinsonism (XDP) is a Mendelian neurodegenerative disease that is endemic to the Philippines and is associated with a founder haplotype. We integrated multiple genome and transcriptome assembly technologies to narrow the causal mutation to the TAF1 locus, which included a SINE-VNTR-Alu (SVA) retrotransposition into intron 32 of the gene. Transcriptome analyses identified decreased expression of the canonical cTAF1 transcript among XDP probands, and de novo assembly across multiple pluripotent stem-cell-derived neuronal lineages discovered aberrant TAF1 transcription that involved alternative splicing and intron retention (IR) in proximity to the SVA that was anti-correlated with overall TAF1 expression. Read More

    Learning from Everyday Images Enables Expert-like Diagnosis of Retinal Diseases.
    Cell 2018 Feb;172(5):893-895
    University of Toronto, Department of Computer Science, Toronto, ON, Canada; The Hospital for Sick Children, Toronto, ON, Canada; Vector Institute, Toronto, ON, Canada. Electronic address:
    Kermany et al. report an application of a neural network trained on millions of everyday images to a database of thousands of retinal tomography images that they gathered and expert labeled, resulting in a rapid and accurate diagnosis of retinal diseases. Read More

    The Unexpected Effects of the Combination of Antibiotics and Immunity.
    Cell 2018 Feb;172(5):891-893
    Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA, USA. Electronic address:
    β-lactam antibiotics and immune enzymes, including lysozyme, kill bacteria by rupturing the cell wall. Curiously, their combination can select for viable, wall-less bacteria. Kawai and colleagues describe the molecular details regarding the emergence of these forms, illustrating a novel and potentially clinically relevant mechanism by which bacteria escape killing by antibiotics. Read More

    Solving Mendelian Mysteries: The Non-coding Genome May Hold the Key.
    Cell 2018 Feb;172(5):889-891
    Sobell Department, Institute of Neurology, University College of London, London, UK.
    Despite revolutionary advances in sequencing approaches, many mendelian disorders have remained unexplained. In this issue of Cell, Aneichyk et al. combine genomic and cell-type-specific transcriptomic data to causally link a non-coding mutation in the ubiquitous TAF1 gene to X-linked dystonia-parkinsonism. Read More

    Antibiotic Resistance.
    Cell 2018 Feb;172(5):1136-1136.e1
    Department of Biology, Technion - Israel Institute of Technology, Haifa 3200003, Israel. Electronic address:
    Bacterial mechanisms of drug resistance operate at sequential lines of defense tackling drug at entry, accumulation, target binding, or downstream toxicity. These mechanisms are encoded by genomic changes ranging in scale from point mutations, through assembly of preexisting genetic elements, to horizontal import of genes from the environment. A many-to-many relationship prevails between resistance mechanisms and the spectrum of genetic changes encoding them. Read More

    Identifying Medical Diagnoses and Treatable Diseases by Image-Based Deep Learning.
    Cell 2018 Feb;172(5):1122-1131.e9
    Guangzhou Women and Children's Medical Center, Guangzhou Medical University, 510005 Guangzhou, China; Shiley Eye Institute, Institute for Engineering in Medicine, Institute for Genomic Medicine, University of California, San Diego, La Jolla, CA 92093, USA; Molecular Medicine Research Center, State Key Laboratory of Biotherapy, The National Clinical Research Center of Senile Disease, West China Hospital, Sichuan University, Chengdu, China; Guangzhou Regenerative Medicine and Health Guangdong Laboratory, 510005 Guangzhou, China; Veterans Administration Healthcare System, San Diego, CA 92037, USA. Electronic address:
    The implementation of clinical-decision support algorithms for medical imaging faces challenges with reliability and interpretability. Here, we establish a diagnostic tool based on a deep-learning framework for the screening of patients with common treatable blinding retinal diseases. Our framework utilizes transfer learning, which trains a neural network with a fraction of the data of conventional approaches. Read More

    Super-Resolution Imaging of the Extracellular Space in Living Brain Tissue.
    Cell 2018 Feb;172(5):1108-1121.e15
    University of Bordeaux, 33077 Bordeaux, France; Interdisciplinary Institute for Neuroscience, CNRS UMR 5297, 33077 Bordeaux, France. Electronic address:
    The extracellular space (ECS) of the brain has an extremely complex spatial organization, which has defied conventional light microscopy. Consequently, despite a marked interest in the physiological roles of brain ECS, its structure and dynamics remain largely inaccessible for experimenters. We combined 3D-STED microscopy and fluorescent labeling of the extracellular fluid to develop super-resolution shadow imaging (SUSHI) of brain ECS in living organotypic brain slices. Read More

    Mapping the Mouse Cell Atlas by Microwell-Seq.
    Cell 2018 Feb;172(5):1091-1107.e17
    Center for Stem Cell and Regenerative Medicine, Zhejiang University School of Medicine, Hangzhou 310058, China; Institute of Hematology, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China; Stem Cell Institute, Zhejiang University, Hangzhou 310058, China. Electronic address:
    Single-cell RNA sequencing (scRNA-seq) technologies are poised to reshape the current cell-type classification system. However, a transcriptome-based single-cell atlas has not been achieved for complex mammalian systems. Here, we developed Microwell-seq, a high-throughput and low-cost scRNA-seq platform using simple, inexpensive devices. Read More

    Modulation of Phase Shift between Wnt and Notch Signaling Oscillations Controls Mesoderm Segmentation.
    Cell 2018 Feb;172(5):1079-1090.e12
    Developmental Biology Unit, European Molecular Biology Laboratory, 69117 Heidelberg, Germany, European Molecular Biology Laboratory, 69117 Heidelberg, Germany. Electronic address:
    How signaling dynamics encode information is a central question in biology. During vertebrate development, dynamic Notch signaling oscillations control segmentation of the presomitic mesoderm (PSM). In mouse embryos, this molecular clock comprises signaling oscillations of several pathways, i. Read More

    Cell-Intrinsic Control of Interneuron Migration Drives Cortical Morphogenesis.
    Cell 2018 Feb;172(5):1063-1078.e19
    GIGA-Neurosciences, University of Liège, C.H.U. Sart Tilman, Liège 4000, Belgium. Electronic address:
    Interneurons navigate along multiple tangential paths to settle into appropriate cortical layers. They undergo a saltatory migration paced by intermittent nuclear jumps whose regulation relies on interplay between extracellular cues and genetic-encoded information. It remains unclear how cycles of pause and movement are coordinated at the molecular level. Read More

    A Hematogenous Route for Medulloblastoma Leptomeningeal Metastases.
    Cell 2018 Feb;172(5):1050-1062.e14
    Developmental and Stem Cell Biology Program, The Hospital for Sick Children, Toronto, ON, Canada; The Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, ON, Canada; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada; Division of Neurosurgery, The Hospital for Sick Children, Toronto, ON, Canada. Electronic address:
    While the preponderance of morbidity and mortality in medulloblastoma patients are due to metastatic disease, most research focuses on the primary tumor due to a dearth of metastatic tissue samples and model systems. Medulloblastoma metastases are found almost exclusively on the leptomeningeal surface of the brain and spinal cord; dissemination is therefore thought to occur through shedding of primary tumor cells into the cerebrospinal fluid followed by distal re-implantation on the leptomeninges. We present evidence for medulloblastoma circulating tumor cells (CTCs) in therapy-naive patients and demonstrate in vivo, through flank xenografting and parabiosis, that medulloblastoma CTCs can spread through the blood to the leptomeningeal space to form leptomeningeal metastases. Read More

    A Non-catalytic Function of SETD1A Regulates Cyclin K and the DNA Damage Response.
    Cell 2018 Feb;172(5):1007-1021.e17
    Department of Pediatric Oncology, Dana-Farber Cancer Institute and Division of Hematology/Oncology, Boston Children's Hospital, Harvard Medical School, Boston, MA 02210, USA; Center for Epigenetics Research, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. Electronic address:
    MLL/SET methyltransferases catalyze methylation of histone 3 lysine 4 and play critical roles in development and cancer. We assessed MLL/SET proteins and found that SETD1A is required for survival of acute myeloid leukemia (AML) cells. Mutagenesis studies and CRISPR-Cas9 domain screening show the enzymatic SET domain is not necessary for AML cell survival but that a newly identified region termed the "FLOS" (functional location on SETD1A) domain is indispensable. Read More

    Rescue of Fragile X Syndrome Neurons by DNA Methylation Editing of the FMR1 Gene.
    Cell 2018 Feb 15;172(5):979-992.e6. Epub 2018 Feb 15.
    Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA; Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02142, USA. Electronic address:
    Fragile X syndrome (FXS), the most common genetic form of intellectual disability in males, is caused by silencing of the FMR1 gene associated with hypermethylation of the CGG expansion mutation in the 5' UTR of FMR1 in FXS patients. Here, we applied recently developed DNA methylation editing tools to reverse this hypermethylation event. Targeted demethylation of the CGG expansion by dCas9-Tet1/single guide RNA (sgRNA) switched the heterochromatin status of the upstream FMR1 promoter to an active chromatin state, restoring a persistent expression of FMR1 in FXS iPSCs. Read More

    Placeholder Nucleosomes Underlie Germline-to-Embryo DNA Methylation Reprogramming.
    Cell 2018 Feb 15;172(5):993-1006.e13. Epub 2018 Feb 15.
    Howard Hughes Medical Institute, Department of Oncological Sciences and Huntsman Cancer Institute, University of Utah School of Medicine, Salt Lake City, UT 84112, USA. Electronic address:
    The fate and function of epigenetic marks during the germline-to-embryo transition is a key issue in developmental biology, with relevance to stem cell programming and transgenerational inheritance. In zebrafish, DNA methylation patterns are programmed in transcriptionally quiescent cleavage embryos; paternally inherited patterns are maintained, whereas maternal patterns are reprogrammed to match the paternal. Here, we provide the mechanism by demonstrating that "Placeholder" nucleosomes, containing histone H2A variant H2A. Read More

    Identification of piRNA Binding Sites Reveals the Argonaute Regulatory Landscape of the C. elegans Germline.
    Cell 2018 Feb 15;172(5):937-951.e18. Epub 2018 Feb 15.
    RNA Therapeutics Institute, University of Massachusetts Medical School, Worcester, MA 01605, USA; Howard Hughes Medical Institute. Electronic address:
    piRNAs (Piwi-interacting small RNAs) engage Piwi Argonautes to silence transposons and promote fertility in animal germlines. Genetic and computational studies have suggested that C. elegans piRNAs tolerate mismatched pairing and in principle could target every transcript. Read More

    Lysozyme Counteracts β-Lactam Antibiotics by Promoting the Emergence of L-Form Bacteria.
    Cell 2018 Feb 15;172(5):1038-1049.e10. Epub 2018 Feb 15.
    Centre for Bacterial Cell Biology, Institute for Cell and Molecular Biosciences, Newcastle University, Newcastle upon Tyne NE2 4AX, UK. Electronic address:
    β-lactam antibiotics inhibit bacterial cell wall assembly and, under classical microbiological culture conditions that are generally hypotonic, induce explosive cell death. Here, we show that under more physiological, osmoprotective conditions, for various Gram-positive bacteria, lysis is delayed or abolished, apparently because inhibition of class A penicillin-binding protein leads to a block in autolytic activity. Although these cells still then die by other mechanisms, exogenous lytic enzymes, such as lysozyme, can rescue viability by enabling the escape of cell wall-deficient "L-form" bacteria. Read More

    NK Cells Stimulate Recruitment of cDC1 into the Tumor Microenvironment Promoting Cancer Immune Control.
    Cell 2018 Feb 8;172(5):1022-1037.e14. Epub 2018 Feb 8.
    Immunobiology Laboratory, The Francis Crick Institute, 1 Midland Road, London NW1 1AT, UK. Electronic address:
    Conventional type 1 dendritic cells (cDC1) are critical for antitumor immunity, and their abundance within tumors is associated with immune-mediated rejection and the success of immunotherapy. Here, we show that cDC1 accumulation in mouse tumors often depends on natural killer (NK) cells that produce the cDC1 chemoattractants CCL5 and XCL1. Similarly, in human cancers, intratumoral CCL5, XCL1, and XCL2 transcripts closely correlate with gene signatures of both NK cells and cDC1 and are associated with increased overall patient survival. Read More

    Chromosome Translocation Inflates Bacillus Forespores and Impacts Cellular Morphology.
    Cell 2018 Feb;172(4):758-770.e14
    Division of Biological Sciences, University of California, San Diego, La Jolla, CA 92093, USA. Electronic address:
    The means by which the physicochemical properties of different cellular components together determine bacterial cell shape remain poorly understood. Here, we investigate a programmed cell-shape change during Bacillus subtilis sporulation, when a rod-shaped vegetative cell is transformed to an ovoid spore. Asymmetric cell division generates a bigger mother cell and a smaller, hemispherical forespore. Read More

    TBK1 at the Crossroads of Inflammation and Energy Homeostasis in Adipose Tissue.
    Cell 2018 Feb;172(4):731-743.e12
    Division of Metabolism and Endocrinology, Department of Medicine, University of California-San Diego, La Jolla, CA 92093, USA; Life Sciences Institute, University of Michigan, Ann Arbor, MI 48109, USA. Electronic address:
    The noncanonical IKK family member TANK-binding kinase 1 (TBK1) is activated by pro-inflammatory cytokines, but its role in controlling metabolism remains unclear. Here, we report that the kinase uniquely controls energy metabolism. Tbk1 expression is increased in adipocytes of HFD-fed mice. Read More

    Fast-Spiking Interneurons Supply Feedforward Control of Bursting, Calcium, and Plasticity for Efficient Learning.
    Cell 2018 Feb;172(4):683-695.e15
    Gladstone Institutes, San Francisco, CA 94158, USA; Department of Neurology, UCSF, San Francisco, CA 94158, USA; Kavli Institute for Fundamental Neuroscience, UCSF, San Francisco, CA 94158, USA; UCSF Weill Institute for Neurosciences, UCSF, San Francisco, CA 94158, USA; Department of Physiology, UCSF, San Francisco, CA 94158, USA. Electronic address:
    Fast-spiking interneurons (FSIs) are a prominent class of forebrain GABAergic cells implicated in two seemingly independent network functions: gain control and network plasticity. Little is known, however, about how these roles interact. Here, we use a combination of cell-type-specific ablation, optogenetics, electrophysiology, imaging, and behavior to describe a unified mechanism by which striatal FSIs control burst firing, calcium influx, and synaptic plasticity in neighboring medium spiny projection neurons (MSNs). Read More

    The Ancient Origins of Neural Substrates for Land Walking.
    Cell 2018 Feb;172(4):667-682.e15
    Neuroscience Institute, Department of Neuroscience and Physiology, NYU School of Medicine, New York, NY 10016, USA. Electronic address:
    Walking is the predominant locomotor behavior expressed by land-dwelling vertebrates, but it is unknown when the neural circuits that are essential for limb control first appeared. Certain fish species display walking-like behaviors, raising the possibility that the underlying circuitry originated in primitive marine vertebrates. We show that the neural substrates of bipedalism are present in the little skate Leucoraja erinacea, whose common ancestor with tetrapods existed ∼420 million years ago. Read More

    The Human Transcription Factors.
    Cell 2018 Feb;172(4):650-665
    Center for Autoimmune Genomics and Etiology (CAGE), Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA; Divisions of Biomedical Informatics and Developmental Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA; Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA. Electronic address:
    Transcription factors (TFs) recognize specific DNA sequences to control chromatin and transcription, forming a complex system that guides expression of the genome. Despite keen interest in understanding how TFs control gene expression, it remains challenging to determine how the precise genomic binding sites of TFs are specified and how TF binding ultimately relates to regulation of transcription. This review considers how TFs are identified and functionally characterized, principally through the lens of a catalog of over 1,600 likely human TFs and binding motifs for two-thirds of them. Read More

    Custom-Made Oocytes to Clone Non-human Primates.
    Cell 2018 Feb;172(4):647-649
    Wellcome Trust/Cancer Research UK Gurdon Institute, University of Cambridge, Tennis Court Road, Cambridge CB2 1QN, UK.
    In this issue of Cell, Liu et al. (2018) report the birth of two healthy cloned macaque monkeys using fetal fibroblasts. By artificially enhancing the arsenal of epigenetic modifiers in the oocyte, the authors overcome the earliest roadblocks that take place during somatic cell nuclear transfer (SCNT). Read More

    Brother's Keeper: Wild-Type Mutant K-Ras Dimers Limit Oncogenesis.
    Cell 2018 Feb;172(4):645-647
    Cancer Research Institute, Beth Israel Deaconess Medical Center, Boston, MA, USA; Department of Medicine, Harvard Medical School, Boston, MA, USA. Electronic address:
    K-Ras is the undisputed champion of oncogenes, yet our ability to interfere with its oncogenic function is hampered by insufficient mechanistic understanding. In this issue of Cell, Ambrogio and colleagues connect the ability of K-Ras to dimerize to the ability of wild-type K-Ras to limit the oncogenic properties of the mutant. Read More

    A Subset of Cancer-Associated Fibroblasts Determines Therapy Resistance.
    Cell 2018 Feb;172(4):643-644
    Laboratory of Translational Oncology, ISREC (Swiss Institute for Experimental Cancer Research), School of Life Sciences, Swiss Federal Institute of Technology Lausanne (EPFL), Lausanne CH-1015, Switzerland.
    While functional heterogeneity of fibroblastic cells populating the tumor microenvironment is increasingly recognized, lack of definitive markers complicates elucidation of roles among ostensibly distinctive fibroblastic states. In this issue of Cell, Su et al. characterize a new pro-tumorigenic cancer-associated fibroblast subset mediating chemoresistance defined and driven by a novel signaling pathway. Read More

    Sort Your Self Out!
    Cell 2018 Feb;172(4):640-642
    Laboratory of Neurogenetics and Neuroinflammation, INSERM UMR1163, Institut Imagine, Paris, France; Paris Descartes University, Sorbonne-Paris-Cité, Institut Imagine, Paris 75015, France; Department of Genetics, Hôpital Necker-Enfants Malades, Assistance Publique-Hôpitaux de Paris, Paris 75015, France; Division of Evolution and Genomic Sciences, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester Academic Health Science Centre, Manchester, UK. Electronic address:
    Discrimination between viral and self-derived nucleic acid species is crucial in maintaining effective antiviral immunity whilst avoiding autoinflammation. Ahmad et al. and Chung et al. Read More

    Building a Stable Relationship: Ensuring Homeostasis among Cell Types within a Tissue.
    Cell 2018 Feb;172(4):638-640
    Howard Hughes Medical Institute, Department of Cellular and Molecular Pharmacology, Center for Systems and Synthetic Biology, University of California, San Francisco, CA 94158, USA. Electronic address:
    Many processes controlling cell growth and death are well characterized for individual cell lineages, but how ensembles of different cell types in a tissue regulate collective size and composition remains unclear. In this issue of Cell, Zhou et al. employ experiments and theory to uncover design principles of tissue homeostasis arising from cross-talk between fibroblasts and macrophages. Read More

    To Bind or Not to Bind: Unravelling GPCR Polypharmacology.
    Cell 2018 Feb;172(4):636-638
    Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville VIC 3052, Australia. Electronic address:
    Interaction of a single drug with multiple targets through "polypharmacology" is increasingly recognized as necessary for treatment of complex diseases, such as schizophrenia. G protein-coupled receptors (GPCRs) are major medicinal targets, and understanding the structural basis of both GPCR drug selectivity and promiscuity could provide novel avenues for drug development. Read More

    Dynamic Ligand Discrimination in the Notch Signaling Pathway.
    Cell 2018 Feb 1;172(4):869-880.e19. Epub 2018 Feb 1.
    Howard Hughes Medical Institute, Division of Biology and Biological Engineering, Department of Applied Physics, California Institute of Technology, Pasadena, CA 91125, USA. Electronic address:
    The Notch signaling pathway comprises multiple ligands that are used in distinct biological contexts. In principle, different ligands could activate distinct target programs in signal-receiving cells, but it is unclear how such ligand discrimination could occur. Here, we show that cells use dynamics to discriminate signaling by the ligands Dll1 and Dll4 through the Notch1 receptor. Read More

    In Situ Structure of Neuronal C9orf72 Poly-GA Aggregates Reveals Proteasome Recruitment.
    Cell 2018 Feb 1;172(4):696-705.e12. Epub 2018 Feb 1.
    Department of Molecular Structural Biology, Max Planck Institute of Biochemistry, 82152 Martinsried, Germany. Electronic address:
    Protein aggregation and dysfunction of the ubiquitin-proteasome system are hallmarks of many neurodegenerative diseases. Here, we address the elusive link between these phenomena by employing cryo-electron tomography to dissect the molecular architecture of protein aggregates within intact neurons at high resolution. We focus on the poly-Gly-Ala (poly-GA) aggregates resulting from aberrant translation of an expanded GGGGCC repeat in C9orf72, the most common genetic cause of amyotrophic lateral sclerosis and frontotemporal dementia. Read More

    Dopamine Secretion Is Mediated by Sparse Active Zone-like Release Sites.
    Cell 2018 Feb 1;172(4):706-718.e15. Epub 2018 Feb 1.
    Department of Neurobiology, Harvard Medical School, Boston, MA 02115, USA. Electronic address:
    Dopamine controls essential brain functions through volume transmission. Different from fast synaptic transmission, where neurotransmitter release and receptor activation are tightly coupled by an active zone, dopamine transmission is widespread and may not necessitate these organized release sites. Here, we determine whether striatal dopamine secretion employs specialized machinery for release. Read More

    Circuit Design Features of a Stable Two-Cell System.
    Cell 2018 Feb 1;172(4):744-757.e17. Epub 2018 Feb 1.
    Howard Hughes Medical Institute, Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06510, USA. Electronic address:
    Cell communication within tissues is mediated by multiple paracrine signals including growth factors, which control cell survival and proliferation. Cells and the growth factors they produce and receive constitute a circuit with specific properties that ensure homeostasis. Here, we used computational and experimental approaches to characterize the features of cell circuits based on growth factor exchange between macrophages and fibroblasts, two cell types found in most mammalian tissues. Read More

    5-HTReceptor Structures Reveal the Structural Basis of GPCR Polypharmacology.
    Cell 2018 Feb 1;172(4):719-730.e14. Epub 2018 Feb 1.
    iHuman Institute, ShanghaiTech University, Shanghai 201210, China; Yunnan Key Laboratory of Stem Cell and Regenerative Medicine, Institute of Molecular and Clinical Medicine, Kunming Medical University, Kunming 650500, China; National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China; School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China. Electronic address:
    Drugs frequently require interactions with multiple targets-via a process known as polypharmacology-to achieve their therapeutic actions. Currently, drugs targeting several serotonin receptors, including the 5-HTreceptor, are useful for treating obesity, drug abuse, and schizophrenia. The competing challenges of developing selective 5-HTreceptor ligands or creating drugs with a defined polypharmacological profile, especially aimed at G protein-coupled receptors (GPCRs), remain extremely difficult. Read More

    CD10GPR77Cancer-Associated Fibroblasts Promote Cancer Formation and Chemoresistance by Sustaining Cancer Stemness.
    Cell 2018 Feb 25;172(4):841-856.e16. Epub 2018 Jan 25.
    Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Medical Research Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, China; Breast Tumor Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, China; Program of Molecular Medicine, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou 510080, China. Electronic address:
    Carcinoma-associated fibroblasts (CAFs) are abundant and heterogeneous stromal cells in tumor microenvironment that are critically involved in cancer progression. Here, we demonstrate that two cell-surface molecules, CD10 and GPR77, specifically define a CAF subset correlated with chemoresistance and poor survival in multiple cohorts of breast and lung cancer patients. CD10GPR77CAFs promote tumor formation and chemoresistance by providing a survival niche for cancer stem cells (CSCs). Read More

    Cloning of Macaque Monkeys by Somatic Cell Nuclear Transfer.
    Cell 2018 Feb 1;172(4):881-887.e7. Epub 2018 Feb 1.
    Institute of Neuroscience, CAS Center for Excellence in Brain Science and Intelligence Technology, State Key Laboratory of Neuroscience, CAS Key Laboratory of Primate Neurobiology, Chinese Academy of Sciences, Shanghai, China. Electronic address:
    Generation of genetically uniform non-human primates may help to establish animal models for primate biology and biomedical research. In this study, we have successfully cloned cynomolgus monkeys (Macaca fascicularis) by somatic cell nuclear transfer (SCNT). We found that injection of H3K9me3 demethylase Kdm4d mRNA and treatment with histone deacetylase inhibitor trichostatin A at one-cell stage following SCNT greatly improved blastocyst development and pregnancy rate of transplanted SCNT embryos in surrogate monkeys. Read More

    Breaching Self-Tolerance to Alu Duplex RNA Underlies MDA5-Mediated Inflammation.
    Cell 2018 Feb 25;172(4):797-810.e13. Epub 2018 Jan 25.
    Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA; Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, MA 02115, USA. Electronic address:
    Aberrant activation of innate immune receptors can cause a spectrum of immune disorders, such as Aicardi-Goutières syndrome (AGS). One such receptor is MDA5, a viral dsRNA sensor that induces antiviral immune response. Using a newly developed RNase-protection/RNA-seq approach, we demonstrate here that constitutive activation of MDA5 in AGS results from the loss of tolerance to cellular dsRNAs formed by Alu retroelements. Read More

    Human ADAR1 Prevents Endogenous RNA from Triggering Translational Shutdown.
    Cell 2018 Feb 25;172(4):811-824.e14. Epub 2018 Jan 25.
    Laboratory of Virology and Infectious Disease, The Rockefeller University, New York, NY 10065, USA. Electronic address:
    Type I interferon (IFN) is produced when host sensors detect foreign nucleic acids, but how sensors differentiate self from nonself nucleic acids, such as double-stranded RNA (dsRNA), is incompletely understood. Mutations in ADAR1, an adenosine-to-inosine editing enzyme of dsRNA, cause Aicardi-Goutières syndrome, an autoinflammatory disorder associated with spontaneous interferon production and neurologic sequelae. We generated ADAR1 knockout human cells to explore ADAR1 substrates and function. Read More

    SnapShot: O-Glycosylation Pathways across Kingdoms.
    Cell 2018 Jan;172(3):632-632.e2
    Copenhagen Center for Glycomics, Department of Cellular and Molecular Medicine, Faculty of Health Sciences, University of Copenhagen, Denmark.
    O-glycosylation is one of the most abundant and diverse types of post-translational modifications of proteins. O-glycans modulate the structure, stability, and function of proteins and serve generalized as well as highly specific roles in most biological processes. This ShapShot presents types of O-glycans found in different organisms and their principle biosynthetic pathways. Read More

    Context-Dependent and Disease-Specific Diversity in Protein Interactions within Stress Granules.
    Cell 2018 Jan;172(3):590-604.e13
    Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA 92093, USA; Stem Cell Program, University of California, San Diego, La Jolla, CA 92093, USA; Institute for Genomic Medicine, University of California, San Diego, La Jolla, CA 92039, USA; Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117593, Singapore; Molecular Engineering Laboratory, A(∗)STAR, Singapore 138673, Singapore. Electronic address:
    Stress granules (SGs) are transient ribonucleoprotein (RNP) aggregates that form during cellular stress and are increasingly implicated in human neurodegeneration. To study the proteome and compositional diversity of SGs in different cell types and in the context of neurodegeneration-linked mutations, we used ascorbate peroxidase (APEX) proximity labeling, mass spectrometry, and immunofluorescence to identify ∼150 previously unknown human SG components. A highly integrated, pre-existing SG protein interaction network in unstressed cells facilitates rapid coalescence into larger SGs. Read More

    Targeting KRAS Mutant Cancers with a Covalent G12C-Specific Inhibitor.
    Cell 2018 Jan;172(3):578-589.e17
    Wellspring Biosciences, San Diego, CA, USA; Kura Oncology, San Diego, CA, USA. Electronic address:
    KRASwas recently identified to be potentially druggable by allele-specific covalent targeting of Cys-12 in vicinity to an inducible allosteric switch II pocket (S-IIP). Success of this approach requires active cycling of KRASbetween its active-GTP and inactive-GDP conformations as accessibility of the S-IIP is restricted only to the GDP-bound state. This strategy proved feasible for inhibiting mutant KRAS in vitro; however, it is uncertain whether this approach would translate to in vivo. Read More

    Mapping Causal Variants with Single-Nucleotide Resolution Reveals Biochemical Drivers of Phenotypic Change.
    Cell 2018 Jan;172(3):478-490.e15
    Department of Chemical and Systems Biology, Stanford University School of Medicine, Stanford, CA 94305, USA; Department of Developmental Biology, Stanford University School of Medicine, Stanford, CA 94305, USA. Electronic address:
    Understanding the sequence determinants that give rise to diversity among individuals and species is the central challenge of genetics. However, despite ever greater numbers of sequenced genomes, most genome-wide association studies cannot distinguish causal variants from linked passenger mutations spanning many genes. We report that this inherent challenge can be overcome in model organisms. Read More

    Functional Classification and Experimental Dissection of Long Noncoding RNAs.
    Cell 2018 Jan;172(3):393-407
    Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Harold C. Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Hamon Center for Regenerative Science and Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA. Electronic address:
    Over the last decade, it has been increasingly demonstrated that the genomes of many species are pervasively transcribed, resulting in the production of numerous long noncoding RNAs (lncRNAs). At the same time, it is now appreciated that many types of DNA regulatory elements, such as enhancers and promoters, regularly initiate bi-directional transcription. Thus, discerning functional noncoding transcripts from a vast transcriptome is a paramount priority, and challenge, for the lncRNA field. Read More

    Meiotic Recombination: Genetics' Good Old Scalpel.
    Cell 2018 Jan;172(3):391-392
    Department of Molecular Genetics, Weizmann Institute of Science, Rehovot, 76100, Israel. Electronic address:
    In the era of genome engineering, a new study returns to classical genetics to decipher genotype-phenotype relationships in unprecedented throughput and with unprecedented accuracy. Capitalizing on natural variation in yeast strains and frequent meiotic recombination, She and Jarosz (2018) dissect and map to nucleotide resolution, simple and complex determinants of diverse phenotypic traits. Read More

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