20,559 results match your criteria Cell[Journal]


TBL1XR1 Mutations Drive Extranodal Lymphoma by Inducing a Pro-tumorigenic Memory Fate.

Cell 2020 Jul 2. Epub 2020 Jul 2.

Division of Hematology/Oncology, Department of Medicine, Weill Cornell Medicine, Cornell University, New York, NY 10021, USA. Electronic address:

The most aggressive B cell lymphomas frequently manifest extranodal distribution and carry somatic mutations in the poorly characterized gene TBL1XR1. Here, we show that TBL1XR1 mutations skew the humoral immune response toward generating abnormal immature memory B cells (MB), while impairing plasma cell differentiation. At the molecular level, TBL1XR1 mutants co-opt SMRT/HDAC3 repressor complexes toward binding the MB cell transcription factor (TF) BACH2 at the expense of the germinal center (GC) TF BCL6, leading to pre-memory transcriptional reprogramming and cell-fate bias. Read More

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http://dx.doi.org/10.1016/j.cell.2020.05.049DOI Listing

BRICseq Bridges Brain-wide Interregional Connectivity to Neural Activity and Gene Expression in Single Animals.

Cell 2020 Jun 29. Epub 2020 Jun 29.

Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA. Electronic address:

Comprehensive analysis of neuronal networks requires brain-wide measurement of connectivity, activity, and gene expression. Although high-throughput methods are available for mapping brain-wide activity and transcriptomes, comparable methods for mapping region-to-region connectivity remain slow and expensive because they require averaging across hundreds of brains. Here we describe BRICseq (brain-wide individual animal connectome sequencing), which leverages DNA barcoding and sequencing to map connectivity from single individuals in a few weeks and at low cost. Read More

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http://dx.doi.org/10.1016/j.cell.2020.05.029DOI Listing

Microglial Remodeling of the Extracellular Matrix Promotes Synapse Plasticity.

Cell 2020 Jun 26. Epub 2020 Jun 26.

Department of Psychiatry and Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA, USA; Kavli Institute for Fundamental Neuroscience, University of California, San Francisco, San Francisco, CA, USA. Electronic address:

Synapse remodeling is essential to encode experiences into neuronal circuits. Here, we define a molecular interaction between neurons and microglia that drives experience-dependent synapse remodeling in the hippocampus. We find that the cytokine interleukin-33 (IL-33) is expressed by adult hippocampal neurons in an experience-dependent manner and defines a neuronal subset primed for synaptic plasticity. Read More

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http://dx.doi.org/10.1016/j.cell.2020.05.050DOI Listing

CD81 Controls Beige Fat Progenitor Cell Growth and Energy Balance via FAK Signaling.

Cell 2020 Jun 26. Epub 2020 Jun 26.

UCSF Diabetes Center, University of California, San Francisco, San Francisco, CA, USA; Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San Francisco, San Francisco, CA, USA; Department of Cell and Tissue Biology, University of California, San Francisco, San Francisco, CA, USA; Beth Israel Deaconess Medical Center, Division of Endocrinology, Diabetes & Metabolism, Harvard Medical School, Boston, MA, USA. Electronic address:

Adipose tissues dynamically remodel their cellular composition in response to external cues by stimulating beige adipocyte biogenesis; however, the developmental origin and pathways regulating this process remain insufficiently understood owing to adipose tissue heterogeneity. Here, we employed single-cell RNA-seq and identified a unique subset of adipocyte progenitor cells (APCs) that possessed the cell-intrinsic plasticity to give rise to beige fat. This beige APC population is proliferative and marked by cell-surface proteins, including PDGFRα, Sca1, and CD81. Read More

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http://dx.doi.org/10.1016/j.cell.2020.06.021DOI Listing

Niche-Selective Inhibition of Pathogenic Th17 Cells by Targeting Metabolic Redundancy.

Cell 2020 Jun 24. Epub 2020 Jun 24.

The Kimmel Center for Biology and Medicine of the Skirball Institute, New York University School of Medicine, New York, NY, USA; Howard Hughes Medical Institute, New York, NY, USA; Department of Pathology, New York University School of Medicine, New York, NY, USA. Electronic address:

Targeting glycolysis has been considered therapeutically intractable owing to its essential housekeeping role. However, the context-dependent requirement for individual glycolytic steps has not been fully explored. We show that CRISPR-mediated targeting of glycolysis in T cells in mice results in global loss of Th17 cells, whereas deficiency of the glycolytic enzyme glucose phosphate isomerase (Gpi1) selectively eliminates inflammatory encephalitogenic and colitogenic Th17 cells, without substantially affecting homeostatic microbiota-specific Th17 cells. Read More

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http://dx.doi.org/10.1016/j.cell.2020.06.014DOI Listing

Structural Basis of Functional Transitions in Mammalian NMDA Receptors.

Cell 2020 Jun 26. Epub 2020 Jun 26.

WM Keck Structural Biology Laboratory, Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA; Watson School of Biological Sciences, Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA. Electronic address:

Excitatory neurotransmission meditated by glutamate receptors including N-methyl-D-aspartate receptors (NMDARs) is pivotal to brain development and function. NMDARs are heterotetramers composed of GluN1 and GluN2 subunits, which bind glycine and glutamate, respectively, to activate their ion channels. Despite importance in brain physiology, the precise mechanisms by which activation and inhibition occur via subunit-specific binding of agonists and antagonists remain largely unknown. Read More

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http://dx.doi.org/10.1016/j.cell.2020.05.052DOI Listing

Origin and Function of Stress-Induced IL-6 in Murine Models.

Cell 2020 Jun 27. Epub 2020 Jun 27.

Department of Medicine (Rheumatology, Allergy & Immunology), Yale University School of Medicine, New Haven, CT, USA; Department of Immunobiology, Yale University School of Medicine, New Haven, CT, USA. Electronic address:

Acute psychological stress has long been known to decrease host fitness to inflammation in a wide variety of diseases, but how this occurs is incompletely understood. Using mouse models, we show that interleukin-6 (IL-6) is the dominant cytokine inducible upon acute stress alone. Stress-inducible IL-6 is produced from brown adipocytes in a beta-3-adrenergic-receptor-dependent fashion. Read More

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http://dx.doi.org/10.1016/j.cell.2020.05.054DOI Listing
June 2020
32.242 Impact Factor

3D Correlative Cryo-Structured Illumination Fluorescence and Soft X-ray Microscopy Elucidates Reovirus Intracellular Release Pathway.

Cell 2020 Jun 27. Epub 2020 Jun 27.

Diamond Light Source, Harwell Science and Innovation Campus, Didcot OX11 0DE, UK. Electronic address:

Imaging of biological matter across resolution scales entails the challenge of preserving the direct and unambiguous correlation of subject features from the macroscopic to the microscopic level. Here, we present a correlative imaging platform developed specifically for imaging cells in 3D under cryogenic conditions by using X-rays and visible light. Rapid cryo-preservation of biological specimens is the current gold standard in sample preparation for ultrastructural analysis in X-ray imaging. Read More

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http://dx.doi.org/10.1016/j.cell.2020.05.051DOI Listing

A Chromatin Accessibility Atlas of the Developing Human Telencephalon.

Cell 2020 Jun 24. Epub 2020 Jun 24.

Department of Psychiatry, Langley Porter Psychiatric Institute, UCSF Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA, USA. Electronic address:

To discover regulatory elements driving the specificity of gene expression in different cell types and regions of the developing human brain, we generated an atlas of open chromatin from nine dissected regions of the mid-gestation human telencephalon, as well as microdissected upper and deep layers of the prefrontal cortex. We identified a subset of open chromatin regions (OCRs), termed predicted regulatory elements (pREs), that are likely to function as developmental brain enhancers. pREs showed temporal, regional, and laminar differences in chromatin accessibility and were correlated with gene expression differences across regions and gestational ages. Read More

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http://dx.doi.org/10.1016/j.cell.2020.06.002DOI Listing

Ribosome Collisions Trigger General Stress Responses to Regulate Cell Fate.

Cell 2020 Jun 23. Epub 2020 Jun 23.

Department of Molecular Biology and Genetics, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Howard Hughes Medical Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. Electronic address:

Problems arising during translation of mRNAs lead to ribosome stalling and collisions that trigger a series of quality control events. However, the global cellular response to ribosome collisions has not been explored. Here, we uncover a function for ribosome collisions in signal transduction. Read More

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http://dx.doi.org/10.1016/j.cell.2020.06.006DOI Listing

Molecular Pathways of Colon Inflammation Induced by Cancer Immunotherapy.

Cell 2020 Jun 25. Epub 2020 Jun 25.

Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Immunology, Harvard Medical School, Boston, MA 02115, USA; Department of Neurology, Brigham & Women's Hospital and Harvard Medical School, Boston, MA 02115, USA. Electronic address:

Checkpoint blockade with antibodies specific for the PD-1 and CTLA-4 inhibitory receptors can induce durable responses in a wide range of human cancers. However, the immunological mechanisms responsible for severe inflammatory side effects remain poorly understood. Here we report a comprehensive single-cell analysis of immune cell populations in colitis, a common and severe side effect of checkpoint blockade. Read More

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http://dx.doi.org/10.1016/j.cell.2020.06.001DOI Listing

SnapShot: Jak-STAT Signaling II.

Cell 2020 Jun;181(7):1696-1696.e1

National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), National Institutes of Health (NIH), Bethesda, MD 20892, USA.

The JAK-STAT pathway is an evolutionarily conserved signal transduction paradigm, providing mechanisms for rapid receptor-to-nucleus communication and transcription control. Discoveries in this field provided insights into primary immunodeficiencies, inherited autoimmune and autoinflammatory diseases, and hematologic and oncologic disorders, giving rise to a new class of drugs, JAK inhibitors (or Jakinibs). Read More

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http://dx.doi.org/10.1016/j.cell.2020.04.052DOI Listing

Metabolic Dynamics and Prediction of Gestational Age and Time to Delivery in Pregnant Women.

Cell 2020 Jun;181(7):1680-1692.e15

Department of Epidemiology Research, Statens Serum Institut, Copenhagen, 2300, Denmark; Department of Clinical Medicine, University of Copenhagen, Copenhagen, 2200, Denmark; Department of Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA. Electronic address:

Metabolism during pregnancy is a dynamic and precisely programmed process, the failure of which can bring devastating consequences to the mother and fetus. To define a high-resolution temporal profile of metabolites during healthy pregnancy, we analyzed the untargeted metabolome of 784 weekly blood samples from 30 pregnant women. Broad changes and a highly choreographed profile were revealed: 4,995 metabolic features (of 9,651 total), 460 annotated compounds (of 687 total), and 34 human metabolic pathways (of 48 total) were significantly changed during pregnancy. Read More

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http://dx.doi.org/10.1016/j.cell.2020.05.002DOI Listing

Molecular Transducers of Physical Activity Consortium (MoTrPAC): Mapping the Dynamic Responses to Exercise.

Cell 2020 Jun;181(7):1464-1474

Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. Electronic address:

Exercise provides a robust physiological stimulus that evokes cross-talk among multiple tissues that when repeated regularly (i.e., training) improves physiological capacity, benefits numerous organ systems, and decreases the risk for premature mortality. Read More

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http://dx.doi.org/10.1016/j.cell.2020.06.004DOI Listing

Mapping the Uncharted Territories of Human Brain Malignancies.

Cell 2020 Jun;181(7):1454-1457

Division of Tumor Biology and Immunology, Netherlands Cancer Institute, Oncode Institute, Amsterdam 1066CX, the Netherlands. Electronic address:

Despite its success in multiple tumor types, immunotherapy remains poorly efficacious in brain malignancies. In this issue of Cell, Friebel et al. and Klemm et al. Read More

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http://dx.doi.org/10.1016/j.cell.2020.06.003DOI Listing

Role of Microbiota-Derived Bile Acids in Enteric Infections.

Cell 2020 Jun;181(7):1452-1454

Department of Medicine, University of Virginia, PO Box 801340, Charlottesville, VA 22908-1340, USA. Electronic address:

In this issue of Cell, Alavi et al. report that infection by Vibrio cholerae is blocked by gut microbiome-mediated hydrolysis of bile acids. Cholera therefore joins amebic dysentery and Clostridioides difficile colitis as enteric infections profoundly influenced by the microbiome's impact on bile acid metabolism. Read More

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http://dx.doi.org/10.1016/j.cell.2020.05.033DOI Listing

Cap-Snatching Leads to Novel Viral Proteins.

Cell 2020 Jun;181(7):1450-1451

Division of Biology, University of California, San Diego, San Diego, CA, USA. Electronic address:

Some negative-sense RNA viruses prime mRNA transcription using host 5' cap sequences, usurping host translational machinery and evading antiviral surveillance. In this issue of Cell, Ho et al. identify an additional consequence of this viral strategy: the acquisition of upstream start codons from host-derived sequences and subsequent translation of novel viral products. Read More

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http://dx.doi.org/10.1016/j.cell.2020.05.044DOI Listing

The Immunoglobulin Superfamily Receptome Defines Cancer-Relevant Networks Associated with Clinical Outcome.

Cell 2020 Jun 23. Epub 2020 Jun 23.

Deparment of Microchemistry, Proteomics and Lipidomics, Genentech, South San Francisco, CA, USA. Electronic address:

Cell surface receptors and their interactions play a central role in physiological and pathological signaling. Despite its clinical relevance, the immunoglobulin superfamily (IgSF) remains uncharacterized and underrepresented in databases. Here, we present a systematic extracellular protein map, the IgSF interactome. Read More

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http://dx.doi.org/10.1016/j.cell.2020.06.007DOI Listing

Recognition of Semaphorin Proteins by P. sordellii Lethal Toxin Reveals Principles of Receptor Specificity in Clostridial Toxins.

Cell 2020 Jun 23. Epub 2020 Jun 23.

Donnelly Centre for Cellular and Biomolecular Research, University of Toronto, Toronto, ON M5S 3E1, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, Canada; Molecular Architecture of Life Program, Canadian Institute for Advanced Research (CIFAR), Toronto, ON M5G 1M1, Canada. Electronic address:

Pathogenic clostridial species secrete potent toxins that induce severe host tissue damage. Paeniclostridium sordellii lethal toxin (TcsL) causes an almost invariably lethal toxic shock syndrome associated with gynecological infections. TcsL is 87% similar to C. Read More

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http://dx.doi.org/10.1016/j.cell.2020.06.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7316060PMC

For Black Scientists, the Sorrow Is Also Personal.

Authors:
Kafui Dzirasa

Cell 2020 Jun 25. Epub 2020 Jun 25.

Departments of Neurobiology, of Psychiatry and Behavioral Sciences, and of Neurosurgery, Duke University Medical Center, Durham, NC 27710, USA; Department of Biomedical Engineering, Duke University, Durham, NC 22208, USA. Electronic address:

I have tried to live in a world that does not see color but have only succeeded in living in a world that does not see me. Read More

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http://dx.doi.org/10.1016/j.cell.2020.06.028DOI Listing

Developing Covalent Protein Drugs via Proximity-Enabled Reactive Therapeutics.

Cell 2020 Jun 18. Epub 2020 Jun 18.

Department of Pharmaceutical Chemistry and the Cardiovascular Research Institute, University of California-San Francisco, San Francisco, CA 94158, USA. Electronic address:

Small molecule covalent drugs provide desirable therapeutic properties over noncovalent ones for treating challenging diseases. The potential of covalent protein drugs, however, remains unexplored due to protein's inability to bind targets covalently. We report a proximity-enabled reactive therapeutics (PERx) approach to generate covalent protein drugs. Read More

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http://dx.doi.org/10.1016/j.cell.2020.05.028DOI Listing

Multimodal Analysis of Composition and Spatial Architecture in Human Squamous Cell Carcinoma.

Cell 2020 Jun 19. Epub 2020 Jun 19.

Program in Epithelial Biology, Stanford University School of Medicine, Stanford, CA 94305, USA; Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA 94305, USA; Veterans Affairs Palo Alto Healthcare System, Palo Alto, CA, USA. Electronic address:

To define the cellular composition and architecture of cutaneous squamous cell carcinoma (cSCC), we combined single-cell RNA sequencing with spatial transcriptomics and multiplexed ion beam imaging from a series of human cSCCs and matched normal skin. cSCC exhibited four tumor subpopulations, three recapitulating normal epidermal states, and a tumor-specific keratinocyte (TSK) population unique to cancer, which localized to a fibrovascular niche. Integration of single-cell and spatial data mapped ligand-receptor networks to specific cell types, revealing TSK cells as a hub for intercellular communication. Read More

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http://dx.doi.org/10.1016/j.cell.2020.05.039DOI Listing

Hybrid Gene Origination Creates Human-Virus Chimeric Proteins during Infection.

Cell 2020 Jun 18;181(7):1502-1517.e23. Epub 2020 Jun 18.

Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Global Health and Emerging Pathogens Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. Electronic address:

RNA viruses are a major human health threat. The life cycles of many highly pathogenic RNA viruses like influenza A virus (IAV) and Lassa virus depends on host mRNA, because viral polymerases cleave 5'-m7G-capped host transcripts to prime viral mRNA synthesis ("cap-snatching"). We hypothesized that start codons within cap-snatched host transcripts could generate chimeric human-viral mRNAs with coding potential. Read More

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http://dx.doi.org/10.1016/j.cell.2020.05.035DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7323901PMC
June 2020
32.242 Impact Factor

Metabolic Fingerprinting Links Oncogenic PIK3CA with Enhanced Arachidonic Acid-Derived Eicosanoids.

Cell 2020 Jun 18;181(7):1596-1611.e27. Epub 2020 Jun 18.

Signalling and Cancer Metabolism Team, Division of Cancer Biology, The Institute of Cancer Research, 237 Fulham Road, London SW3 6JB, UK; Division of Systems Medicine, Department of Metabolism Digestion and Reproduction, Imperial College London, London SW7 2AZ, UK. Electronic address:

Oncogenic transformation is associated with profound changes in cellular metabolism, but whether tracking these can improve disease stratification or influence therapy decision-making is largely unknown. Using the iKnife to sample the aerosol of cauterized specimens, we demonstrate a new mode of real-time diagnosis, coupling metabolic phenotype to mutant PIK3CA genotype. Oncogenic PIK3CA results in an increase in arachidonic acid and a concomitant overproduction of eicosanoids, acting to promote cell proliferation beyond a cell-autonomous manner. Read More

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http://dx.doi.org/10.1016/j.cell.2020.05.053DOI Listing

Pan-Genome of Wild and Cultivated Soybeans.

Cell 2020 Jun 15. Epub 2020 Jun 15.

State Key Laboratory of Plant Cell and Chromosome Engineering, Institute of Genetics and Developmental Biology, Innovation Academy for Seed Design, Chinese Academy of Sciences, Beijing 100101, China; College of Advanced Agriculture Sciences, University of Chinese Academy of Sciences, Beijing 100049, China. Electronic address:

Soybean is one of the most important vegetable oil and protein feed crops. To capture the entire genomic diversity, it is needed to construct a complete high-quality pan-genome from diverse soybean accessions. In this study, we performed individual de novo genome assemblies for 26 representative soybeans that were selected from 2,898 deeply sequenced accessions. Read More

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http://dx.doi.org/10.1016/j.cell.2020.05.023DOI Listing
June 2020
32.242 Impact Factor

A SARS-CoV-2 Infection Model in Mice Demonstrates Protection by Neutralizing Antibodies.

Cell 2020 Jun 10. Epub 2020 Jun 10.

Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA; Department of Pathology & Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA; Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, MO 63110, USA; The Andrew M. and Jane M. Bursky Center for Human Immunology & Immunotherapy Programs, Washington University School of Medicine, St. Louis, MO 63110, USA. Electronic address:

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused a pandemic with millions of human infections. One limitation to the evaluation of potential therapies and vaccines to inhibit SARS-CoV-2 infection and ameliorate disease is the lack of susceptible small animals in large numbers. Commercially available laboratory strains of mice are not readily infected by SARS-CoV-2 because of species-specific differences in their angiotensin-converting enzyme 2 (ACE2) receptors. Read More

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http://dx.doi.org/10.1016/j.cell.2020.06.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7284254PMC

Major Impacts of Widespread Structural Variation on Gene Expression and Crop Improvement in Tomato.

Cell 2020 Jun 8. Epub 2020 Jun 8.

Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA; Howard Hughes Medical Institute, Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA. Electronic address:

Structural variants (SVs) underlie important crop improvement and domestication traits. However, resolving the extent, diversity, and quantitative impact of SVs has been challenging. We used long-read nanopore sequencing to capture 238,490 SVs in 100 diverse tomato lines. Read More

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http://dx.doi.org/10.1016/j.cell.2020.05.021DOI Listing

CBASS Immunity Uses CARF-Related Effectors to Sense 3'-5'- and 2'-5'-Linked Cyclic Oligonucleotide Signals and Protect Bacteria from Phage Infection.

Cell 2020 Jun 4. Epub 2020 Jun 4.

Department of Microbiology, Harvard Medical School, Boston, MA 02115, USA; Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA 02115, USA; Parker Institute for Cancer Immunotherapy at Dana-Farber Cancer Institute, Boston, MA 02115, USA. Electronic address:

cGAS/DncV-like nucleotidyltransferase (CD-NTase) enzymes are immune sensors that synthesize nucleotide second messengers and initiate antiviral responses in bacterial and animal cells. Here, we discover Enterobacter cloacae CD-NTase-associated protein 4 (Cap4) as a founding member of a diverse family of >2,000 bacterial receptors that respond to CD-NTase signals. Structures of Cap4 reveal a promiscuous DNA endonuclease domain activated through ligand-induced oligomerization. Read More

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http://dx.doi.org/10.1016/j.cell.2020.05.019DOI Listing

Structural Basis of Low-pH-Dependent Lysosomal Cholesterol Egress by NPC1 and NPC2.

Cell 2020 Jun 11. Epub 2020 Jun 11.

Department of Molecular Biology, Princeton University, Princeton, NJ 08544, USA. Electronic address:

Lysosomal cholesterol egress requires two proteins, NPC1 and NPC2, whose defects are responsible for Niemann-Pick disease type C (NPC). Here, we present systematic structural characterizations that reveal the molecular basis for low-pH-dependent cholesterol delivery from NPC2 to the transmembrane (TM) domain of NPC1. At pH 8. Read More

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http://dx.doi.org/10.1016/j.cell.2020.05.020DOI Listing

How Support of Early Career Researchers Can Reset Science in the Post-COVID19 World.

Cell 2020 Jun 12;181(7):1445-1449. Epub 2020 Jun 12.

Department of Neurosurgery, Stanford University School of Medicine, Palo Alto, CA 94305, USA.

The COVID19 crisis has magnified the issues plaguing academic science, but it has also provided the scientific establishment with an unprecedented opportunity to reset. Shoring up the foundation of academic science will require a concerted effort between funding agencies, universities, and the public to rethink how we support scientists, with a special emphasis on early career researchers. Read More

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http://dx.doi.org/10.1016/j.cell.2020.05.045DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7291965PMC
June 2020
32.242 Impact Factor

Determinants of Base Editing Outcomes from Target Library Analysis and Machine Learning.

Cell 2020 Jun 9. Epub 2020 Jun 9.

Merkin Institute of Transformative Technologies in Healthcare, Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA; Department of Chemistry and Chemical Biology, Harvard University, Cambridge, MA 02138, USA; Howard Hughes Medical Institute, Harvard University, Cambridge, MA 02138, USA. Electronic address:

Although base editors are widely used to install targeted point mutations, the factors that determine base editing outcomes are not well understood. We characterized sequence-activity relationships of 11 cytosine and adenine base editors (CBEs and ABEs) on 38,538 genomically integrated targets in mammalian cells and used the resulting outcomes to train BE-Hive, a machine learning model that accurately predicts base editing genotypic outcomes (R ≈ 0.9) and efficiency (R ≈ 0. Read More

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http://dx.doi.org/10.1016/j.cell.2020.05.037DOI Listing
June 2020
32.242 Impact Factor

SnapShot: Meiosis - Prophase I.

Cell 2020 Jun;181(6):1442-1442.e1

Department of Genetics, Blavatnik Institute, Harvard Medical School, Boston, MA 02115, USA.

Meiosis is the specialized cell division that generates haploid gametes and is therefore essential for sexual reproduction. This SnapShot encompasses key events taking place during prophase I of meiosis that are required for achieving proper chromosome segregation and highlights how these are both conserved and diverged throughout five different species. To view this SnapShot, open or download the PDF. Read More

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http://dx.doi.org/10.1016/j.cell.2020.04.038DOI Listing

A Reply to ''Evidence that STK19 Is Not an NRAS-Dependent Melanoma Driver".

Cell 2020 Jun;181(6):1406-1409.e2

Department of Pharmacology and Experimental Therapeutics, Boston University School of Medicine, Boston, MA 02118, USA. Electronic address:

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http://dx.doi.org/10.1016/j.cell.2020.04.029DOI Listing

Evidence That STK19 Is Not an NRAS-dependent Melanoma Driver.

Cell 2020 Jun;181(6):1395-1405.e11

Mechanisms of Transcription Laboratory, The Francis Crick Institute, 1 Midland Road, London NW1 1AT, UK. Electronic address:

STK19 was proposed to be a cancer driver, and recent work by Yin et al. (2019) in Cell suggested that the frequently recurring STK19 D89N substitution represents a gain-of-function change, allowing increased phosphorylation of NRAS to enhance melanocyte transformation. Here we show that the STK19 gene has been incorrectly annotated, and that the expressed protein is 110 amino acids shorter than indicated by current databases. Read More

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http://dx.doi.org/10.1016/j.cell.2020.04.014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7298618PMC

The Physiology, Pathology, and Potential Therapeutic Applications of the TREM2 Signaling Pathway.

Cell 2020 Jun;181(6):1207-1217

Department of Immunology, Weizmann Institute, Rehovot 76100, Israel. Electronic address:

Alzheimer's disease, obesity-related metabolic syndrome, and cancer are the leading causes of death and among the most costly medical conditions in the Western world. In all three cases, recent discoveries establish the TREM2 receptor as a major pathology-induced immune signaling hub that senses tissue damage and activates robust immune remodeling in response to it. In this review, we summarize and question what is known and remains to be discovered about TREM2 signaling pathway, track the consequences of its activation in physiological niches and pathological contexts, and highlight the promising potential of therapeutic manipulation of TREM2 signaling. Read More

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http://dx.doi.org/10.1016/j.cell.2020.05.003DOI Listing

An Autonomous Oscillation Times and Executes Centriole Biogenesis.

Cell 2020 Jun 11;181(7):1566-1581.e27. Epub 2020 Jun 11.

Sir William Dunn School of Pathology, University of Oxford, Oxford OX1 3RE, UK. Electronic address:

The accurate timing and execution of organelle biogenesis is crucial for cell physiology. Centriole biogenesis is regulated by Polo-like kinase 4 (Plk4) and initiates in S-phase when a daughter centriole grows from the side of a pre-existing mother. Here, we show that a Plk4 oscillation at the base of the growing centriole initiates and times centriole biogenesis to ensure that centrioles grow at the right time and to the right size. Read More

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http://dx.doi.org/10.1016/j.cell.2020.05.018DOI Listing
June 2020
32.242 Impact Factor

Population Structure, Stratification, and Introgression of Human Structural Variation.

Cell 2020 Jun 10. Epub 2020 Jun 10.

Wellcome Sanger Institute, Hinxton CB10 1SA, UK. Electronic address:

Structural variants contribute substantially to genetic diversity and are important evolutionarily and medically, but they are still understudied. Here we present a comprehensive analysis of structural variation in the Human Genome Diversity panel, a high-coverage dataset of 911 samples from 54 diverse worldwide populations. We identify, in total, 126,018 variants, 78% of which were not identified in previous global sequencing projects. Read More

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http://dx.doi.org/10.1016/j.cell.2020.05.024DOI Listing

Structural Basis for RNA Replication by the SARS-CoV-2 Polymerase.

Cell 2020 May 22. Epub 2020 May 22.

Shanghai Institute for Advanced Immunochemical Studies and School of Life Science and Technology, ShanghaiTech University, Shanghai, China; Laboratory of Structural Biology, School of Life Sciences and School of Medicine, Tsinghua University, Beijing, China; National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, CAS, Beijing, China. Electronic address:

Nucleotide analog inhibitors, including broad-spectrum remdesivir and favipiravir, have shown promise in in vitro assays and some clinical studies for COVID-19 treatment, this despite an incomplete mechanistic understanding of the viral RNA-dependent RNA polymerase nsp12 drug interactions. Here, we examine the molecular basis of SARS-CoV-2 RNA replication by determining the cryo-EM structures of the stalled pre- and post- translocated polymerase complexes. Compared with the apo complex, the structures show notable structural rearrangements happening to nsp12 and its co-factors nsp7 and nsp8 to accommodate the nucleic acid, whereas there are highly conserved residues in nsp12, positioning the template and primer for an in-line attack on the incoming nucleotide. Read More

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http://dx.doi.org/10.1016/j.cell.2020.05.034DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7242921PMC

Personalized Mapping of Drug Metabolism by the Human Gut Microbiome.

Cell 2020 Jun 10;181(7):1661-1679.e22. Epub 2020 Jun 10.

Department of Molecular Biology, Princeton University, Princeton, NJ 08544, USA; Department of Chemical and Biological Engineering, Princeton University, Princeton, NJ 08544, USA. Electronic address:

The human gut microbiome harbors hundreds of bacterial species with diverse biochemical capabilities. Dozens of drugs have been shown to be metabolized by single isolates from the gut microbiome, but the extent of this phenomenon is rarely explored in the context of microbial communities. Here, we develop a quantitative experimental framework for mapping the ability of the human gut microbiome to metabolize small molecule drugs: Microbiome-Derived Metabolism (MDM)-Screen. Read More

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http://dx.doi.org/10.1016/j.cell.2020.05.001DOI Listing

SARS-CoV-2 Reverse Genetics Reveals a Variable Infection Gradient in the Respiratory Tract.

Cell 2020 May 27. Epub 2020 May 27.

Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA; Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA. Electronic address:

The mode of acquisition and causes for the variable clinical spectrum of coronavirus disease 2019 (COVID-19) remain unknown. We utilized a reverse genetics system to generate a GFP reporter virus to explore severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pathogenesis and a luciferase reporter virus to demonstrate sera collected from SARS and COVID-19 patients exhibited limited cross-CoV neutralization. High-sensitivity RNA in situ mapping revealed the highest angiotensin-converting enzyme 2 (ACE2) expression in the nose with decreasing expression throughout the lower respiratory tract, paralleled by a striking gradient of SARS-CoV-2 infection in proximal (high) versus distal (low) pulmonary epithelial cultures. Read More

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http://dx.doi.org/10.1016/j.cell.2020.05.042DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7250779PMC

A Viral Exposure Signature Defines Early Onset of Hepatocellular Carcinoma.

Cell 2020 Jun 9. Epub 2020 Jun 9.

Laboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA; Liver Cancer Program, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA. Electronic address:

Hepatocellular carcinoma (HCC) is an aggressive malignancy with its global incidence and mortality rate continuing to rise, although early detection and surveillance are suboptimal. We performed serological profiling of the viral infection history in 899 individuals from an NCI-UMD case-control study using a synthetic human virome, VirScan. We developed a viral exposure signature and validated the results in a longitudinal cohort with 173 at-risk patients who had long-term follow-up for HCC development. Read More

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http://dx.doi.org/10.1016/j.cell.2020.05.038DOI Listing
June 2020
32.242 Impact Factor

Science Has a Racism Problem.

Authors:

Cell 2020 Jun 9;181(7):1443-1444. Epub 2020 Jun 9.

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http://dx.doi.org/10.1016/j.cell.2020.06.009DOI Listing

Pathogenesis of SARS-CoV-2 in Transgenic Mice Expressing Human Angiotensin-Converting Enzyme 2.

Cell 2020 May 21. Epub 2020 May 21.

CAS Key Laboratory of Special Pathogens, Wuhan Institute of Virology, Center for Biosafety Mega-Science, Chinese Academy of Sciences, Wuhan, Hubei, People's Republic of China. Electronic address:

COVID-19 has spread worldwide since 2019 and is now a severe threat to public health. We previously identified the causative agent as a novel SARS-related coronavirus (SARS-CoV-2) that uses human angiotensin-converting enzyme 2 (hACE2) as the entry receptor. Here, we successfully developed a SARS-CoV-2 hACE2 transgenic mouse (HFH4-hACE2 in C3B6 mice) infection model. Read More

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http://dx.doi.org/10.1016/j.cell.2020.05.027DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7241398PMC
May 2020
32.242 Impact Factor

Behavior- and Modality-General Representation of Confidence in Orbitofrontal Cortex.

Cell 2020 Jun 2. Epub 2020 Jun 2.

Cold Spring Harbor Laboratory, 1 Bungtown Road, Cold Spring Harbor, NY 11724, USA; Watson School of Biological Sciences, 1 Bungtown Road, Cold Spring Harbor, NY 11724, USA; Department of Neuroscience and Department of Psychiatry, Washington University in St. Louis, St. Louis, MO 63110, USA. Electronic address:

Every decision we make is accompanied by a sense of confidence about its likely outcome. This sense informs subsequent behavior, such as investing more-whether time, effort, or money-when reward is more certain. A neural representation of confidence should originate from a statistical computation and predict confidence-guided behavior. Read More

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http://dx.doi.org/10.1016/j.cell.2020.05.022DOI Listing

Intergenerationally Maintained Histone H4 Lysine 16 Acetylation Is Instructive for Future Gene Activation.

Cell 2020 Jun 3. Epub 2020 Jun 3.

Max Planck Institute of Immunobiology and Epigenetics, 79108 Freiburg im Breisgau, Germany. Electronic address:

Before zygotic genome activation (ZGA), the quiescent genome undergoes reprogramming to transition into the transcriptionally active state. However, the mechanisms underlying euchromatin establishment during early embryogenesis remain poorly understood. Here, we show that histone H4 lysine 16 acetylation (H4K16ac) is maintained from oocytes to fertilized embryos in Drosophila and mammals. Read More

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http://dx.doi.org/10.1016/j.cell.2020.05.026DOI Listing

Sleep Loss Can Cause Death through Accumulation of Reactive Oxygen Species in the Gut.

Cell 2020 Jun 4;181(6):1307-1328.e15. Epub 2020 Jun 4.

Department of Neurobiology, Harvard Medical School, Boston, MA 02115, USA. Electronic address:

The view that sleep is essential for survival is supported by the ubiquity of this behavior, the apparent existence of sleep-like states in the earliest animals, and the fact that severe sleep loss can be lethal. The cause of this lethality is unknown. Here we show, using flies and mice, that sleep deprivation leads to accumulation of reactive oxygen species (ROS) and consequent oxidative stress, specifically in the gut. Read More

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http://dx.doi.org/10.1016/j.cell.2020.04.049DOI Listing