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    Rethinking Unconventional Translation in Neurodegeneration.
    Cell 2017 Nov;171(5):994-1000
    Ludwig Institute for Cancer Research, University of California at San Diego, La Jolla, CA 92093, USA; Department of Neurosciences, University of California at San Diego, La Jolla, CA 92093, USA; Department of Cellular and Molecular Medicine, University of California at San Diego, La Jolla, CA 92093, USA. Electronic address:
    Eukaryotic translation is tightly regulated to ensure that protein production occurs at the right time and place. Recent studies on abnormal repeat proteins, especially in age-dependent neurodegenerative diseases caused by nucleotide repeat expansion, have highlighted or identified two forms of unconventional translation initiation: usage of AUG-like sites (near cognates) or repeat-associated non-AUG (RAN) translation. We discuss how repeat proteins may differ due to not just unconventional initiation, but also ribosomal frameshifting and/or imperfect repeat DNA replication, expansion, and repair, and we highlight how research on translation of repeats may uncover insights into the biology of translation and its contribution to disease. Read More

    Risky Business: The Circuits that Impact Stress-Induced Decision-Making.
    Cell 2017 Nov;171(5):992-993
    Department of Psychiatry, Yale University School of Medicine, New Haven, CT 06510, USA; Child Study Center, Yale University School of Medicine, New Haven, CT 06510, USA.
    How does stress promote risky decision-making? Friedman et al. find that stress disrupts inhibition of striatal circuits by prefrontal cortex, rendering animals insensitive to potential losses. This may help explain how stress contributes to substance abuse and how it can disinhibit automatic behaviors, such as tics in Tourette syndrome. Read More

    Tuning Biased GPCR Signaling for Physiological Gain.
    Cell 2017 Nov;171(5):989-991
    Department of Anesthesiology, Division of Basic Research, Washington University School of Medicine, St. Louis, MO 63110, USA; Department of Neuroscience, Washington University School of Medicine, St. Louis, MO 63110, USA; Department of Psychiatry, Washington University School of Medicine, St. Louis, MO 63110, USA; Division of Biology and Biomedical Sciences, Washington University School of Medicine, St. Louis, MO 63110, USA; Washington University Pain Center, Washington University School of Medicine, St. Louis, MO 63110, USA. Electronic address:
    Effective and safe doses of opiate painkillers, like morphine, can be limited by respiratory depression. Schmid et al. (2017) now present a quantitative method to design ligands and correlate GPCR signaling bias to the dose separation between therapeutic and adverse effects in animals. Read More

    Cancer Evolution: No Room for Negative Selection.
    Cell 2017 Nov;171(5):987-989
    Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, NY 10065, USA; Division of Hematology and Medical Oncology, Institute for Computational Biomedicine, Weill Cornell Medicine, New York, NY 10065, USA; New York Genome Center, New York, NY 10013, USA. Electronic address:
    In this issue of Cell, Martincorena et al. and Campbell et al. interrogated the selection dynamics during tumor evolution using large-scale genomics datasets. Read More

    Core Clinical Data Elements for Cancer Genomic Repositories: A Multi-stakeholder Consensus.
    Cell 2017 Nov;171(5):982-986
    Genentech, San Francisco, CA 94080, USA.
    The Center for Medical Technology Policy and the Molecular Evidence Development Consortium gathered a diverse group of more than 50 stakeholders to develop consensus on a core set of data elements and values essential to understanding the clinical utility of molecularly targeted therapies in oncology. Read More

    First Approved Kinase Inhibitor for AML.
    Cell 2017 Nov;171(5):981
    South Australian Health and Medical Research Institute (SAHMRI) and University of Adelaide, Australia.
    Activating mutations of FLT3 occur in about 30% of acute myeloid leukemia (AML) cases and are associated with relapse and poor prognosis. Midostaurin is the first drug approved for AML since 2000, and the first multi-kinase inhibitor approved for the FLT3-mutant subtype. To view this Bench to Bedside, open or download the PDF. Read More

    SnapShot: Functions of Endoplasmic Reticulum Membrane Contact Sites.
    Cell 2017 Nov;171(5):1224-1224.e1
    Department of Molecular, Cellular, and Developmental Biology, University of Colorado, Boulder, CO 80309, USA.
    The endoplasmic reticulum (ER) consists of the nuclear envelope and a reticulated interconnected network of tubules and sheets. ER sheets are studded with ribosomes and provide the entryway for proteins into the secretory pathway. ER tubules move dynamically on microtubules and form membrane contact sites with other organelles, where membranes are tethered, but not fused. Read More

    Classifying Drosophila Olfactory Projection Neuron Subtypes by Single-Cell RNA Sequencing.
    Cell 2017 Nov;171(5):1206-1220.e22
    Department of Biology and Howard Hughes Medical Institute, Stanford University, Stanford, CA 94305, USA. Electronic address:
    The definition of neuronal type and how it relates to the transcriptome are open questions. Drosophila olfactory projection neurons (PNs) are among the best-characterized neuronal types: different PN classes target dendrites to distinct olfactory glomeruli, while PNs of the same class exhibit indistinguishable anatomical and physiological properties. Using single-cell RNA sequencing, we comprehensively characterized the transcriptomes of most PN classes and unequivocally mapped transcriptomes to specific olfactory function for six classes. Read More

    Chronic Stress Alters Striosome-Circuit Dynamics, Leading to Aberrant Decision-Making.
    Cell 2017 Nov;171(5):1191-1205.e28
    McGovern Institute for Brain Research and Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, MA 02139, USA. Electronic address:
    Effective evaluation of costs and benefits is a core survival capacity that in humans is considered as optimal, "rational" decision-making. This capacity is vulnerable in neuropsychiatric disorders and in the aftermath of chronic stress, in which aberrant choices and high-risk behaviors occur. We report that chronic stress exposure in rodents produces abnormal evaluation of costs and benefits resembling non-optimal decision-making in which choices of high-cost/high-reward options are sharply increased. Read More

    Bias Factor and Therapeutic Window Correlate to Predict Safer Opioid Analgesics.
    Cell 2017 Nov;171(5):1165-1175.e13
    Departments of Molecular Medicine and Neuroscience, The Scripps Research Institute, Jupiter, FL 33458, USA. Electronic address:
    Biased agonism has been proposed as a means to separate desirable and adverse drug responses downstream of G protein-coupled receptor (GPCR) targets. Herein, we describe structural features of a series of mu-opioid-receptor (MOR)-selective agonists that preferentially activate receptors to couple to G proteins or to recruit βarrestin proteins. By comparing relative bias for MOR-mediated signaling in each pathway, we demonstrate a strong correlation between the respiratory suppression/antinociception therapeutic window in a series of compounds spanning a wide range of signaling bias. Read More

    NRF1 Is an ER Membrane Sensor that Is Central to Cholesterol Homeostasis.
    Cell 2017 Nov;171(5):1094-1109.e15
    Department of Genetics and Complex Diseases and Sabri Ülker Center, Harvard TH Chan School of Public Health, Boston, MA 02115, USA; Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA. Electronic address:
    Cholesterol is a critical nutrient requiring tight constraint in the endoplasmic reticulum (ER) due to its uniquely challenging biophysical properties. While the mechanisms by which the ER defends against cholesterol insufficiency are well described, it remains unclear how the ER senses and effectively defends against cholesterol excess. Here, we identify the ER-bound transcription factor nuclear factor erythroid 2 related factor-1, Nrf1/Nfe2L1, as a critical mediator of this process. Read More

    Structural Basis of Mitochondrial Transcription Initiation.
    Cell 2017 Nov;171(5):1072-1081.e10
    Department of Molecular Biology, Max Planck Institute for Biophysical Chemistry, Am Fassberg 11, 37077 Göttingen, Germany. Electronic address:
    Transcription in human mitochondria is driven by a single-subunit, factor-dependent RNA polymerase (mtRNAP). Despite its critical role in both expression and replication of the mitochondrial genome, transcription initiation by mtRNAP remains poorly understood. Here, we report crystal structures of human mitochondrial transcription initiation complexes assembled on both light and heavy strand promoters. Read More

    Specification of Physiologic and Disease States by Distinct Proteins and Protein Conformations.
    Cell 2017 Nov;171(5):1001-1014
    Ann Romney Center for Neurologic Disease, Department of Neurology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA; Harvard Stem Cell Institute, Cambridge, MA 02138, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA. Electronic address:
    Protein conformational states-from intrinsically disordered ensembles to amyloids that underlie the self-templating, infectious properties of prion-like proteins-have attracted much attention. Here, we highlight the diversity, including differences in biophysical properties, that drive distinct biological functions and pathologies among self-templating proteins. Advances in chemical genomics, gene editing, and model systems now permit deconstruction of the complex interplay between these protein states and the host factors that react to them. Read More

    Lysophosphatidylcholine Regulates Sexual Stage Differentiation in the Human Malaria Parasite Plasmodium falciparum.
    Cell 2017 Nov 2. Epub 2017 Nov 2.
    Wellcome Centre for Molecular Parasitology, Institute of Infection, Immunity & Inflammation, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow G12 8QQ, UK; Harvard T.H. Chan School of Public Health, Department of Immunology and Infectious Diseases, Boston, MA 02155, USA. Electronic address:
    Transmission represents a population bottleneck in the Plasmodium life cycle and a key intervention target of ongoing efforts to eradicate malaria. Sexual differentiation is essential for this process, as only sexual parasites, called gametocytes, are infective to the mosquito vector. Gametocyte production rates vary depending on environmental conditions, but external stimuli remain obscure. Read More

    Light Controls Protein Localization through Phytochrome-Mediated Alternative Promoter Selection.
    Cell 2017 Nov 7. Epub 2017 Nov 7.
    Faculty of Agriculture, Kyushu University, Fukuoka 812-8581, Japan; PRESTO, JST, Saitama 332-0012, Japan. Electronic address:
    Alternative promoter usage is a proteome-expanding mechanism that allows multiple pre-mRNAs to be transcribed from a single gene. The impact of this mechanism on the proteome and whether it is positively exploited in normal organismal responses remain unclear. We found that the plant photoreceptor phytochrome induces genome-wide changes in alternative promoter selection in Arabidopsis thaliana. Read More

    MHC-I Genotype Restricts the Oncogenic Mutational Landscape.
    Cell 2017 Oct 20. Epub 2017 Oct 20.
    Department of Medicine, Division of Medical Genetics, University of California San Diego, La Jolla, CA 92093, USA; Bioinformatics and Systems Biology Program, University of California San Diego, La Jolla, CA 92093, USA; Moores Cancer Center, University of California San Diego, La Jolla, CA 92093, USA; Cancer Cell Map Initiative (CCMI), University of California San Diego, La Jolla, CA 92093, USA.
    MHC-I molecules expose the intracellular protein content on the cell surface, allowing T cells to detect foreign or mutated peptides. The combination of six MHC-I alleles each individual carries defines the sub-peptidome that can be effectively presented. We applied this concept to human cancer, hypothesizing that oncogenic mutations could arise in gaps in personal MHC-I presentation. Read More

    Granzyme B Disrupts Central Metabolism and Protein Synthesis in Bacteria to Promote an Immune Cell Death Program.
    Cell 2017 Nov 26;171(5):1125-1137.e11. Epub 2017 Oct 26.
    Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, MA 02115, USA; Department of Pediatrics, Harvard Medical School, Boston, MA 02115, USA. Electronic address:
    Human cytotoxic lymphocytes kill intracellular microbes. The cytotoxic granule granzyme proteases released by cytotoxic lymphocytes trigger oxidative bacterial death by disrupting electron transport, generating superoxide anion and inactivating bacterial oxidative defenses. However, they also cause non-oxidative cell death because anaerobic bacteria are also killed. Read More

    Neuronal Representation of Social Information in the Medial Amygdala of Awake Behaving Mice.
    Cell 2017 Nov 26;171(5):1176-1190.e17. Epub 2017 Oct 26.
    Howard Hughes Medical Institute, Harvard University, Cambridge, MA, USA; Department of Molecular and Cellular Biology and Center for Brain Science, Harvard University, Cambridge, MA, USA. Electronic address:
    The medial amygdala (MeA) plays a critical role in processing species- and sex-specific signals that trigger social and defensive behaviors. However, the principles by which this deep brain structure encodes social information is poorly understood. We used a miniature microscope to image the Ca(2+) dynamics of large neural ensembles in awake behaving mice and tracked the responses of MeA neurons over several months. Read More

    Force Triggers YAP Nuclear Entry by Regulating Transport across Nuclear Pores.
    Cell 2017 Oct 25. Epub 2017 Oct 25.
    Institute for Bioengineering of Catalonia (IBEC), The Barcelona Institute of Science and Technology (BIST), 08028 Barcelona, Spain; University of Barcelona, 08028 Barcelona, Spain. Electronic address:
    YAP is a mechanosensitive transcriptional activator with a critical role in cancer, regeneration, and organ size control. Here, we show that force applied to the nucleus directly drives YAP nuclear translocation by decreasing the mechanical restriction of nuclear pores to molecular transport. Exposure to a stiff environment leads cells to establish a mechanical connection between the nucleus and the cytoskeleton, allowing forces exerted through focal adhesions to reach the nucleus. Read More

    Allele-Specific HLA Loss and Immune Escape in Lung Cancer Evolution.
    Cell 2017 Oct 21. Epub 2017 Oct 21.
    Cancer Research UK Lung Cancer Centre of Excellence, University College London Cancer Institute, Paul O'Gorman Building, 72 Huntley Street, London WC1E 6BT, UK; Translational Cancer Therapeutics Laboratory, The Francis Crick Institute, 1 Midland Rd, London NW1 1AT, UK. Electronic address:
    Immune evasion is a hallmark of cancer. Losing the ability to present neoantigens through human leukocyte antigen (HLA) loss may facilitate immune evasion. However, the polymorphic nature of the locus has precluded accurate HLA copy-number analysis. Read More

    Cytosolic Protein Vms1 Links Ribosome Quality Control to Mitochondrial and Cellular Homeostasis.
    Cell 2017 Oct 24. Epub 2017 Oct 24.
    Department of Cellular Biochemistry, Max Planck Institute of Biochemistry, Am Klopferspitz 18, 82152 Martinsried, Germany; Division of Cell Biology, Biomedical Center, Faculty of Medicine, University of Munich, Großhaderner Strasse 9, 82152 Martinsried, Germany. Electronic address:
    Eukaryotic cells have evolved extensive protein quality-control mechanisms to remove faulty translation products. Here, we show that yeast cells continually produce faulty mitochondrial polypeptides that stall on the ribosome during translation but are imported into the mitochondria. The cytosolic protein Vms1, together with the E3 ligase Ltn1, protects against the mitochondrial toxicity of these proteins and maintains cell viability under respiratory conditions. Read More

    Membrane Microdomain Disassembly Inhibits MRSA Antibiotic Resistance.
    Cell 2017 Oct 26. Epub 2017 Oct 26.
    National Centre for Biotechnology, Spanish National Research Council (CNB-CSIC), 28049 Madrid, Spain; Research Centre for Infectious Diseases (ZINF), University of Würzburg, 97080 Würzburg, Germany; Institute for Molecular Infection Biology (IMIB), University of Würzburg, 97080 Würzburg, Germany; National Centre for Biotechnology, Spanish National Research Council (CNB-CSIC), Darwin 3, Campus de Cantoblanco, 28049 Madrid, Spain. Electronic address:
    A number of bacterial cell processes are confined functional membrane microdomains (FMMs), structurally and functionally similar to lipid rafts of eukaryotic cells. How bacteria organize these intricate platforms and what their biological significance is remain important questions. Using the pathogen methicillin-resistant Staphylococcus aureus (MRSA), we show here that membrane-carotenoid interaction with the scaffold protein flotillin leads to FMM formation, which can be visualized using super-resolution array tomography. Read More

    Ancestral Circuits for the Coordinated Modulation of Brain State.
    Cell 2017 Nov 2. Epub 2017 Nov 2.
    Department of Bioengineering, Stanford University, Stanford, CA 94305, USA; CNC Program, Stanford University, Stanford, CA 94305, USA; Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, CA 94305, USA; Howard Hughes Medical Institute, Stanford University, Stanford, CA 94305, USA. Electronic address:
    Internal states of the brain profoundly influence behavior. Fluctuating states such as alertness can be governed by neuromodulation, but the underlying mechanisms and cell types involved are not fully understood. We developed a method to globally screen for cell types involved in behavior by integrating brain-wide activity imaging with high-content molecular phenotyping and volume registration at cellular resolution. Read More

    Composition and Regulation of the Cellular Repertoire of SCF Ubiquitin Ligases.
    Cell 2017 Oct 26. Epub 2017 Oct 26.
    Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA 91125, USA; Howard Hughes Medical Institute, California Institute of Technology, Pasadena, CA 91125, USA. Electronic address:
    SCF (Skp1-Cullin-F-box) ubiquitin ligases comprise several dozen modular enzymes that have diverse roles in biological regulation. SCF enzymes share a common catalytic core containing Cul1⋅Rbx1, which is directed toward different substrates by a variable substrate receptor (SR) module comprising 1 of 69 F-box proteins bound to Skp1. Despite the broad cellular impact of SCF enzymes, important questions remain about the architecture and regulation of the SCF repertoire, including whether SRs compete for Cul1 and, if so, how this competition is managed. Read More

    Comprehensive and Integrated Genomic Characterization of Adult Soft Tissue Sarcomas.
    • Authors:
    • ,
    Cell 2017 Nov;171(4):950-965.e28
    Cancer Genome Atlas Program Office, National Cancer Institute at NIH, 31 Center Drive, Bldg. 31, Suite 3A20, Bethesda, MD 20892, USA.
    Sarcomas are a broad family of mesenchymal malignancies exhibiting remarkable histologic diversity. We describe the multi-platform molecular landscape of 206 adult soft tissue sarcomas representing 6 major types. Along with novel insights into the biology of individual sarcoma types, we report three overarching findings: (1) unlike most epithelial malignancies, these sarcomas (excepting synovial sarcoma) are characterized predominantly by copy-number changes, with low mutational loads and only a few genes (TP53, ATRX, RB1) highly recurrently mutated across sarcoma types; (2) within sarcoma types, genomic and regulomic diversity of driver pathways defines molecular subtypes associated with patient outcome; and (3) the immune microenvironment, inferred from DNA methylation and mRNA profiles, associates with outcome and may inform clinical trials of immune checkpoint inhibitors. Read More

    Plexin-B2 Mediates Physiologic and Pathologic Functions of Angiogenin.
    Cell 2017 Nov;171(4):849-864.e25
    Molecular Oncology Research Institute, Tufts Medical Center, 800 Washington Street, Boston, MA 02111, USA; Department of Pathology, Harvard Medical School, 77 Avenue Louis Pasteur, Boston, MA 02115, USA; Graduate Program in Cellular and Molecular Physiology, Sackler School of Graduate Biomedical Sciences, Tufts University, 145 Harrison Avenue, Boston, MA 02111, USA; Graduate Program in Biochemistry, Sackler School of Graduate Biomedical Sciences, Tufts University, 145 Harrison Avenue, Boston, MA 02111, USA. Electronic address:
    Angiogenin (ANG) is a secreted ribonuclease (RNase) with cell-type- and context-specific roles in growth, survival, and regeneration. Although these functions require receptor-mediated endocytosis and appropriate subcellular localization, the identity of the cell surface receptor remains undefined. Here, we show that plexin-B2 (PLXNB2) is the functional receptor for ANG in endothelial, cancer, neuronal, and normal hematopoietic and leukemic stem and progenitor cells. Read More

    Synaptic Neurexin Complexes: A Molecular Code for the Logic of Neural Circuits.
    Cell 2017 Nov;171(4):745-769
    Department of Molecular and Cellular Physiology and Howard Hughes Medical Institute, Stanford University Medical School, 265 Campus Drive, CA 94305-5453, USA. Electronic address:
    Synapses are specialized junctions between neurons in brain that transmit and compute information, thereby connecting neurons into millions of overlapping and interdigitated neural circuits. Here, we posit that the establishment, properties, and dynamics of synapses are governed by a molecular logic that is controlled by diverse trans-synaptic signaling molecules. Neurexins, expressed in thousands of alternatively spliced isoforms, are central components of this dynamic code. Read More

    Can U Turn ILC2s Up?
    Cell 2017 Nov;171(4):742-744
    Laboratory of Mucosal Immunology, The Rockefeller University, 1230 York Ave, New York, NY 10065, USA. Electronic address:
    Innate lymphoid cells (ILCs) are tuned to quickly respond to and amplify tissue-specific signals. Work of three independent groups in Nature uncovers a novel mode of inflammatory communication between ILC2s and neurons at mucosal surfaces. Read More

    Cancer Evolution during Immunotherapy.
    Cell 2017 Nov;171(4):740-742
    Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, USA; Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, USA. Electronic address:
    Immune checkpoint blockade has revolutionized cancer treatment. In this issue of Cell, insights from a longitudinal multi-omics analysis of the largest yet-reported cohort of melanoma patients reveal how tumor and immunity co-evolve during anti-PD-1 therapy. Read More

    Uniformity from Diversity: Vast-Range Light Sensing in a Single Neuron Type.
    Cell 2017 Nov;171(4):738-740
    Department of Neurobiology, Stanford University School of Medicine, Stanford, CA, USA; Department of Ophthalmology, Stanford University School of Medicine, Stanford, CA, USA. Electronic address:
    The brightness of our visual environment varies tremendously from day to night. In this issue of Cell, Milner and Do describe how the population of retinal neurons responsible for entrainment of the brain's circadian clock cooperate to encode irradiance across a wide range of ambient-light intensities. Read More

    A Missing Link to Vitamin B12 Metabolism.
    Cell 2017 Nov;171(4):736-737
    Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, NC 27710, USA. Electronic address:
    Nearly 3% of the human population carries bi-allelic loss-of-function variants in the gene encoding CLYBL. While largely healthy, these individuals exhibit reduced circulating vitamin B12 levels. In this issue of Cell, Shen and colleagues uncover the metabolic role of CLYBL, linking its function to B12 metabolism and the immunomodulatory metabolite, itaconate. Read More

    Edaravone: A new drug approved for ALS.
    Cell 2017 Nov;171(4):725
    Brain Science Institute and Dept of Neurology, Johns Hopkins University, Baltimore, MD 21218, USA. Electronic address:
    Amyotrophic lateral sclerosis (ALS) is a progressive, adult onset neurodegenerative disease that is always fatal. The history of ALS drug discovery is fraught with many stops and starts. It took 22 years after the FDA approval of the anti-excitotoxic drug Riluzole before another drug was found to be effective in altering ALS progression: the anti-oxidant Edaravone. Read More

    Universal Patterns of Selection in Cancer and Somatic Tissues.
    Cell 2017 Nov 19;171(5):1029-1041.e21. Epub 2017 Oct 19.
    Wellcome Trust Sanger Institute, Hinxton CB10 1SA, Cambridgeshire, UK; Department of Haematology, University of Cambridge, Cambridge CB2 2XY, UK. Electronic address:
    Cancer develops as a result of somatic mutation and clonal selection, but quantitative measures of selection in cancer evolution are lacking. We adapted methods from molecular evolution and applied them to 7,664 tumors across 29 cancer types. Unlike species evolution, positive selection outweighs negative selection during cancer development. Read More

    A Genetic Tool to Track Protein Aggregates and Control Prion Inheritance.
    Cell 2017 Nov 19;171(4):966-979.e18. Epub 2017 Oct 19.
    Biological Design Center, Boston University, Boston, MA 02215, USA; Department of Biomedical Engineering, Boston University, Boston, MA 02215, USA; Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, MA 02115, USA. Electronic address:
    Protein aggregation is a hallmark of many diseases but also underlies a wide range of positive cellular functions. This phenomenon has been difficult to study because of a lack of quantitative and high-throughput cellular tools. Here, we develop a synthetic genetic tool to sense and control protein aggregation. Read More

    Comprehensive Analysis of Hypermutation in Human Cancer.
    Cell 2017 Nov 19;171(5):1042-1056.e10. Epub 2017 Oct 19.
    Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, ON, Canada; Department of Paediatric Laboratory Medicine, The Hospital for Sick Children, Toronto, ON, Canada; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada. Electronic address:
    We present an extensive assessment of mutation burden through sequencing analysis of >81,000 tumors from pediatric and adult patients, including tumors with hypermutation caused by chemotherapy, carcinogens, or germline alterations. Hypermutation was detected in tumor types not previously associated with high mutation burden. Replication repair deficiency was a major contributing factor. Read More

    ILC1 Confer Early Host Protection at Initial Sites of Viral Infection.
    Cell 2017 Nov 19;171(4):795-808.e12. Epub 2017 Oct 19.
    Immunology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. Electronic address:
    Infection is restrained by the concerted activation of tissue-resident and circulating immune cells. Whether tissue-resident lymphocytes confer early antiviral immunity at local sites of primary infection prior to the initiation of circulating responses is not well understood. Furthermore, the kinetics of initial antiviral responses at sites of infection remain unclear. Read More

    Synthetic RNA-Based Immunomodulatory Gene Circuits for Cancer Immunotherapy.
    Cell 2017 Nov 19;171(5):1138-1150.e15. Epub 2017 Oct 19.
    Synthetic Biology Group, Research Laboratory of Electronics , Massachusetts Institute of Technology, Cambridge, MA 02139, USA; David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Synthetic Biology Center, Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Department of Electrical Engineering and Computer Science , Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Biophysics Program, Harvard University, Boston, MA 02115, USA; Center for Microbiome Informatics and Therapeutics, Massachusetts Institute of Technology, Cambridge, MA 02139, USA. Electronic address:
    Despite its success in several clinical trials, cancer immunotherapy remains limited by the rarity of targetable tumor-specific antigens, tumor-mediated immune suppression, and toxicity triggered by systemic delivery of potent immunomodulators. Here, we present a proof-of-concept immunomodulatory gene circuit platform that enables tumor-specific expression of immunostimulators, which could potentially overcome these limitations. Our design comprised de novo synthetic cancer-specific promoters and, to enhance specificity, an RNA-based AND gate that generates combinatorial immunomodulatory outputs only when both promoters are mutually active. Read More

    The Human Knockout Gene CLYBL Connects Itaconate to Vitamin B12.
    Cell 2017 Nov 19;171(4):771-782.e11. Epub 2017 Oct 19.
    Howard Hughes Medical Institute and Department of Molecular Biology, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Systems Biology, Harvard Medical School, Boston, MA 02115, USA; Broad Institute, Cambridge, MA 02141, USA. Electronic address:
    CLYBL encodes a ubiquitously expressed mitochondrial enzyme, conserved across all vertebrates, whose cellular activity and pathway assignment are unknown. Its homozygous loss is tolerated in seemingly healthy individuals, with reduced circulating B12 levels being the only and consistent phenotype reported to date. Here, by combining enzymology, structural biology, and activity-based metabolomics, we report that CLYBL operates as a citramalyl-CoA lyase in mammalian cells. Read More

    STING Senses Microbial Viability to Orchestrate Stress-Mediated Autophagy of the Endoplasmic Reticulum.
    Cell 2017 Nov 19;171(4):809-823.e13. Epub 2017 Oct 19.
    The Jill Roberts Institute for Research in Inflammatory Bowel Disease, Weill Cornell Medicine, Cornell University, New York, NY 10021, USA; Joan and Sanford I. Weill Department of Medicine, Weill Cornell Medicine, Cornell University, New York, NY 10021, USA; Department of Microbiology and Immunology, Weill Cornell Medicine, Cornell University, New York, NY 10021, USA; Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, Cornell University, New York, NY 10021, USA; Immunology and Microbial Pathogenesis Program, Weill Cornell Graduate School of Medical Sciences, Weill Cornell Medicine, Cornell University, New York, NY 10021, USA. Electronic address:
    Constitutive cell-autonomous immunity in metazoans predates interferon-inducible immunity and comprises primordial innate defense. Phagocytes mobilize interferon-inducible responses upon engagement of well-characterized signaling pathways by pathogen-associated molecular patterns (PAMPs). The signals controlling deployment of constitutive cell-autonomous responses during infection have remained elusive. Read More

    Wild Mouse Gut Microbiota Promotes Host Fitness and Improves Disease Resistance.
    Cell 2017 Nov 19;171(5):1015-1028.e13. Epub 2017 Oct 19.
    Immunology Section, Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, DHHS, Bethesda, MD 20892, USA. Electronic address:
    Laboratory mice, while paramount for understanding basic biological phenomena, are limited in modeling complex diseases of humans and other free-living mammals. Because the microbiome is a major factor in mammalian physiology, we aimed to identify a naturally evolved reference microbiome to better recapitulate physiological phenomena relevant in the natural world outside the laboratory. Among 21 distinct mouse populations worldwide, we identified a closely related wild relative to standard laboratory mouse strains. Read More

    Selective Inhibition of FOXO1 Activator/Repressor Balance Modulates Hepatic Glucose Handling.
    Cell 2017 Nov 19;171(4):824-835.e18. Epub 2017 Oct 19.
    Naomi Berrie Diabetes Center, Columbia University, New York, NY 10032, USA; Department of Medicine, Columbia University, New York, NY 10032, USA. Electronic address:
    Insulin resistance is a hallmark of diabetes and an unmet clinical need. Insulin inhibits hepatic glucose production and promotes lipogenesis by suppressing FOXO1-dependent activation of G6pase and inhibition of glucokinase, respectively. The tight coupling of these events poses a dual conundrum: mechanistically, as the FOXO1 corepressor of glucokinase is unknown, and clinically, as inhibition of glucose production is predicted to increase lipogenesis. Read More

    Early-Life Gene Expression in Neurons Modulates Lasting Epigenetic States.
    Cell 2017 Nov 19;171(5):1151-1164.e16. Epub 2017 Oct 19.
    Department of Neurobiology, Harvard Medical School, Boston, MA 02115, USA. Electronic address:
    In mammals, the environment plays a critical role in promoting the final steps in neuronal development during the early postnatal period. While epigenetic factors are thought to contribute to this process, the underlying molecular mechanisms remain poorly understood. Here, we show that in the brain during early life, the DNA methyltransferase DNMT3A transiently binds across transcribed regions of lowly expressed genes, and its binding specifies the pattern of DNA methylation at CA sequences (mCA) within these genes. Read More

    SnapShot: Angiopoietins and Their Functions.
    Cell 2017 Oct;171(3):724-724.e1
    University of Helsinki and Wihuri Research Institute, 00290 Helsinki, Finland.
    Angiopoietins signal through TIE receptors to control both developmental and homeostatic processes that can go awry in genetic diseases and cancer. This SnapShot illustrates key elements of angiopoietin signaling in normal and disease contexts. Read More

    A Gut Microbial Mimic that Hijacks Diabetogenic Autoreactivity to Suppress Colitis.
    Cell 2017 Oct;171(3):655-667.e17
    Julia McFarlane Diabetes Research Centre (JMDRC), University of Calgary, Calgary AB T2N 4N1, Canada; Autoimmunity Research Group, Institut D'Investigacions Biomèdiques August Pi i Sunyer, 08036 Barcelona, Spain; Department of Microbiology, Immunology, and Infectious Diseases, Snyder Institute for Chronic Diseases, University of Calgary, Calgary AB T2N 4N1, Canada. Electronic address:
    The gut microbiota contributes to the development of normal immunity but, when dysregulated, can promote autoimmunity through various non-antigen-specific effects on pathogenic and regulatory lymphocytes. Here, we show that an integrase expressed by several species of the gut microbial genus Bacteroides encodes a low-avidity mimotope of the pancreatic β cell autoantigen islet-specific glucose-6-phosphatase-catalytic-subunit-related protein (IGRP206-214). Studies in germ-free mice monocolonized with integrase-competent, integrase-deficient, and integrase-transgenic Bacteroides demonstrate that the microbial epitope promotes the recruitment of diabetogenic CD8+ T cells to the gut. Read More

    mTORC1 Activator SLC38A9 Is Required to Efflux Essential Amino Acids from Lysosomes and Use Protein as a Nutrient.
    Cell 2017 Oct;171(3):642-654.e12
    Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA; Department of Biology, Massachusetts Institute of Technology, 9 Cambridge Center, Cambridge, MA 02142, USA; Howard Hughes Medical Institute, Cambridge, MA 02139, USA; Koch Institute for Integrative Cancer Research, 77 Massachusetts Avenue, Cambridge, MA 02139, USA; Broad Institute of MIT and Harvard, 7 Cambridge Center, Cambridge, MA 02142, USA. Electronic address:
    The mTORC1 kinase is a master growth regulator that senses many environmental cues, including amino acids. Activation of mTORC1 by arginine requires SLC38A9, a poorly understood lysosomal membrane protein with homology to amino acid transporters. Here, we validate that SLC38A9 is an arginine sensor for the mTORC1 pathway, and we uncover an unexpectedly central role for SLC38A9 in amino acid homeostasis. Read More

    PEBP1 Wardens Ferroptosis by Enabling Lipoxygenase Generation of Lipid Death Signals.
    Cell 2017 Oct;171(3):628-641.e26
    Department of Environmental and Occupational Health, Center for Free Radical and Antioxidant Health, University of Pittsburgh, Pittsburgh, PA, USA; Department of Chemistry, University of Pittsburgh, Pittsburgh, PA, USA; Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, PA, USA; Department of Radiation Oncology, University of Pittsburgh, Pittsburgh, PA, USA. Electronic address:
    Ferroptosis is a form of programmed cell death that is pathogenic to several acute and chronic diseases and executed via oxygenation of polyunsaturated phosphatidylethanolamines (PE) by 15-lipoxygenases (15-LO) that normally use free polyunsaturated fatty acids as substrates. Mechanisms of the altered 15-LO substrate specificity are enigmatic. We sought a common ferroptosis regulator for 15LO. Read More

    Multiscale 3D Genome Rewiring during Mouse Neural Development.
    Cell 2017 Oct;171(3):557-572.e24
    Institute of Human Genetics, UMR 9002 of the CNRS and the Université de Montpellier, 34396 Montpellier, France. Electronic address:
    Chromosome conformation capture technologies have revealed important insights into genome folding. Yet, how spatial genome architecture is related to gene expression and cell fate remains unclear. We comprehensively mapped 3D chromatin organization during mouse neural differentiation in vitro and in vivo, generating the highest-resolution Hi-C maps available to date. Read More

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