7,734 results match your criteria Cell reports[Journal]


MZT Proteins Form Multi-Faceted Structural Modules in the γ-Tubulin Ring Complex.

Cell Rep 2020 Jun;31(13):107791

Laboratory of Chemistry and Cell Biology, The Rockefeller University, 1230 York Avenue, New York, NY 10065, USA. Electronic address:

Microtubule organization depends on the γ-tubulin ring complex (γ-TuRC), a ∼2.3-MDa nucleation factor comprising an asymmetric assembly of γ-tubulin and GCP2-GCP6. However, it is currently unclear how the γ-TuRC-associated microproteins MZT1 and MZT2 contribute to the structure and regulation of the holocomplex. Read More

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http://dx.doi.org/10.1016/j.celrep.2020.107791DOI Listing

Visual Experience Influences Dendritic Orientation but Is Not Required for Asymmetric Wiring of the Retinal Direction Selective Circuit.

Cell Rep 2020 Jun;31(13):107844

Helen Wills Neuroscience Institute, University of California, Berkeley, Berkeley, CA 94720, USA; Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA 94720, USA. Electronic address:

Changes in dendritic morphology in response to activity have long been thought to be a critical component of how neural circuits develop to properly encode sensory information. Ventral-preferring direction-selective ganglion cells (vDSGCs) have asymmetric dendrites oriented along their preferred direction, and this has been hypothesized to play a critical role in their tuning. Here we report the surprising result that visual experience is critical for the alignment of vDSGC dendrites to their preferred direction. Read More

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http://dx.doi.org/10.1016/j.celrep.2020.107844DOI Listing

Alzheimer's Patient Microglia Exhibit Enhanced Aging and Unique Transcriptional Activation.

Cell Rep 2020 Jun;31(13):107843

Department of Neuroscience, Genentech, Inc., South San Francisco, CA, USA. Electronic address:

Damage-associated microglia (DAM) profiles observed in Alzheimer's disease (AD)-related mouse models reflect an activation state that could modulate AD risk or progression. To learn whether human AD microglia (HAM) display a similar profile, we develop a method for purifying cell types from frozen cerebrocortical tissues for RNA-seq analysis, allowing better transcriptome coverage than typical single-nucleus RNA-seq approaches. The HAM profile we observe bears little resemblance to the DAM profile. Read More

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http://dx.doi.org/10.1016/j.celrep.2020.107843DOI Listing

Small-Molecule Control of Super-Mendelian Inheritance in Gene Drives.

Cell Rep 2020 Jun;31(13):107841

Chemical Biology and Therapeutics Science, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Department of Medicine, Harvard Medical School, Boston, MA 02115, USA; Divisions of Renal Medicine and Engineering, Brigham and Women's Hospital, Boston, MA 02115, USA. Electronic address:

Synthetic CRISPR-based gene-drive systems have tremendous potential in public health and agriculture, such as for fighting vector-borne diseases or suppressing crop pest populations. These elements can rapidly spread in a population by breaching the inheritance limit of 50% dictated by Mendel's law of gene segregation, making them a promising tool for population engineering. However, current technologies lack control over their propagation capacity, and there are important concerns about potential unchecked spreading. Read More

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http://dx.doi.org/10.1016/j.celrep.2020.107841DOI Listing

Molecular Stressors Engender Protein Connectivity Dysfunction through Aberrant N-Glycosylation of a Chaperone.

Cell Rep 2020 Jun;31(13):107840

Chemical Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. Electronic address:

Stresses associated with disease may pathologically remodel the proteome by both increasing interaction strength and altering interaction partners, resulting in proteome-wide connectivity dysfunctions. Chaperones play an important role in these alterations, but how these changes are executed remains largely unknown. Our study unveils a specific N-glycosylation pattern used by a chaperone, Glucose-regulated protein 94 (GRP94), to alter its conformational fitness and stabilize a state most permissive for stable interactions with proteins at the plasma membrane. Read More

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http://dx.doi.org/10.1016/j.celrep.2020.107840DOI Listing

Caspase Activation and Caspase-Mediated Cleavage of APP Is Associated with Amyloid β-Protein-Induced Synapse Loss in Alzheimer's Disease.

Cell Rep 2020 Jun;31(13):107839

Department of Neurosciences, University of California, San Diego, La Jolla, CA 92037, USA; Departments of Medicine and Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117549, Singapore. Electronic address:

Amyloid β-protein (Aβ) toxicity is hypothesized to play a seminal role in Alzheimer's disease (AD) pathogenesis. However, it remains unclear how Aβ causes synaptic dysfunction and synapse loss. We hypothesize that one mechanism of Aβ-induced synaptic injury is related to the cleavage of amyloid β precursor protein (APP) at position D664 by caspases that release the putatively cytotoxic C31 peptide. Read More

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http://dx.doi.org/10.1016/j.celrep.2020.107839DOI Listing

Atrx Deletion in Neurons Leads to Sexually Dimorphic Dysregulation of miR-137 and Spatial Learning and Memory Deficits.

Cell Rep 2020 Jun;31(13):107838

Children's Health Research Institute, London, ON, Canada; Lawson Health Research Institute, London, ON, Canada; Department of Paediatrics, Western University, London, ON, Canada; Department of Anatomy & Cell Biology, Western University, London, ON, Canada; Department of Oncology, Western University, London, ON, Canada. Electronic address:

ATRX gene mutations have been identified in syndromic and non-syndromic intellectual disabilities in humans. ATRX is known to maintain genomic stability in neuroprogenitor cells, but its function in differentiated neurons and memory processes remains largely unresolved. Here, we show that the deletion of neuronal Atrx in mice leads to distinct hippocampal structural defects, fewer presynaptic vesicles, and an enlarged postsynaptic area at CA1 apical dendrite-axon junctions. Read More

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http://dx.doi.org/10.1016/j.celrep.2020.107838DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7326465PMC

Structure of Human ATG9A, the Only Transmembrane Protein of the Core Autophagy Machinery.

Cell Rep 2020 Jun;31(13):107837

Unit on Structural and Chemical Biology of Membrane Proteins, Neurosciences and Cellular and Structural Biology Division, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892, USA. Electronic address:

Autophagy is a catabolic process involving capture of cytoplasmic materials into double-membraned autophagosomes that subsequently fuse with lysosomes for degradation of the materials by lysosomal hydrolases. One of the least understood components of the autophagy machinery is the transmembrane protein ATG9. Here, we report a cryoelectron microscopy structure of the human ATG9A isoform at 2. Read More

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http://dx.doi.org/10.1016/j.celrep.2020.107837DOI Listing

Promiscuous Binding of Microprotein Mozart1 to γ-Tubulin Complex Mediates Specific Subcellular Targeting to Control Microtubule Array Formation.

Cell Rep 2020 Jun;31(13):107836

Molecular and Cell Biology, Taiwan International Graduate Program, Academia Sinica and National Defense Medical Center, Taipei 11490, Taiwan; Institute of Molecular Biology, Academia Sinica, Taipei 11529, Taiwan; Institute of Biochemistry and Molecular Biology, College of Life Sciences, National Yang-Ming University, Taipei 11221, Taiwan. Electronic address:

How γ-tubulin ring complex (γ-TuRC), a master template for microtubule nucleation, is spatially and temporally regulated for the assembly of new microtubule arrays remains unclear. Here, we report that an evolutionarily conserved microprotein, Mozart1 (Mzt1), regulates subcellular targeting and microtubule formation activity of γ-TuRC at different cell cycle stages. Crystal structures of protein complexes demonstrate that Mzt1 promiscuously interacts with the N-terminal domains of multiple γ-tubulin complex protein subunits in γ-TuRC via an intercalative binding mode. Read More

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http://dx.doi.org/10.1016/j.celrep.2020.107836DOI Listing

Vcp Overexpression and Leucine Supplementation Increase Protein Synthesis and Improve Fear Memory and Social Interaction of Nf1 Mutant Mice.

Cell Rep 2020 Jun;31(13):107835

Institute of Molecular Biology, Academia Sinica, Taipei, 11529, Taiwan, Republic of China. Electronic address:

Neurofibromatosis type 1 (NF1) is a dominant genetic disorder manifesting, in part, as cognitive defects. Previous study indicated that neurofibromin (NF1 protein) interacts with valosin-containing protein (VCP)/P97 to control dendritic spine formation, but the mechanism is unknown. Here, using Nf1 mice and transgenic mice overexpressing wild-type Vcp/p97, we demonstrate that neurofibromin acts with VCP to control endoplasmic reticulum (ER) formation and consequent protein synthesis and regulates dendritic spine formation, thereby modulating contextual fear memory and social interaction. Read More

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http://dx.doi.org/10.1016/j.celrep.2020.107835DOI Listing

Zeb2 Is a Regulator of Astrogliosis and Functional Recovery after CNS Injury.

Cell Rep 2020 Jun;31(13):107834

Burke Neurological Institute, 785 Mamaroneck Avenue, White Plains, NY 10605, USA; Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, 1600 York Avenue, New York, NY 10065, USA; Department of Chemistry and Life Science, United States Military Academy, West Point, NY 10996, USA. Electronic address:

The astrocytic response to injury is characterized on the cellular level, but our understanding of the molecular mechanisms controlling the cellular processes is incomplete. The astrocytic response to injury is similar to wound-healing responses in non-neural tissues that involve epithelial-to-mesenchymal transitions (EMTs) and upregulation in ZEB transcription factors. Here we show that injury-induced astrogliosis increases EMT-related genes expression, including Zeb2, and long non-coding RNAs, including Zeb2os, which facilitates ZEB2 protein translation. Read More

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http://dx.doi.org/10.1016/j.celrep.2020.107834DOI Listing

Labeling and Characterization of Human GLP-1-Secreting L-cells in Primary Ileal Organoid Culture.

Cell Rep 2020 Jun;31(13):107833

Wellcome Trust - MRC Institute of Metabolic Science Metabolic Research Laboratories, Addenbrooke's Hospital, Hills Road, Cambridge CB2 0QQ, UK. Electronic address:

Glucagon-like peptide-1 (GLP-1) from intestinal L-cells stimulates insulin secretion and reduces appetite after food ingestion, and it is the basis for drugs against type-2 diabetes and obesity. Drugs targeting L- and other enteroendocrine cells are under development, with the aim to mimic endocrine effects of gastric bypass surgery, but they are difficult to develop without human L-cell models. Human ileal organoids, engineered by CRISPR-Cas9, express the fluorescent protein Venus in the proglucagon locus, enabling maintenance of live, identifiable human L-cells in culture. Read More

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http://dx.doi.org/10.1016/j.celrep.2020.107833DOI Listing

Discovering How Heme Controls Genome Function Through Heme-omics.

Cell Rep 2020 Jun;31(13):107832

Department of Cell and Regenerative Biology, UW-Madison Blood Research Program, Carbone Cancer Center, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA. Electronic address:

Protein ensembles control genome function by establishing, maintaining, and deconstructing cell-type-specific chromosomal landscapes. A plethora of small molecules orchestrate cellular functions and therefore may link physiological processes with genome biology. The metabolic enzyme and hemoglobin cofactor heme induces proteolysis of a transcriptional repressor, Bach1, and regulates gene expression post-transcriptionally. Read More

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http://dx.doi.org/10.1016/j.celrep.2020.107832DOI Listing

Landscape of Non-canonical Cysteines in Human V Repertoire Revealed by Immunogenetic Analysis.

Cell Rep 2020 Jun;31(13):107831

Biologics Research, Sanofi, Framingham, MA 01701, USA. Electronic address:

Human antibody repertoire data captured through next-generation sequencing (NGS) has enabled deeper insights into B cell immunogenetics and paratope diversity. By analyzing large public NGS datasets, we map the landscape of non-canonical cysteines in human variable heavy-chain domains (Vs) at the repertoire level. We identify remarkable usage of non-canonical cysteines within the heavy-chain complementarity-determining region 3 (CDR-H3) and other CDRs and framework regions. Read More

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http://dx.doi.org/10.1016/j.celrep.2020.107831DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7326410PMC

Senescence, Necrosis, and Apoptosis Govern Circulating Cell-free DNA Release Kinetics.

Cell Rep 2020 Jun;31(13):107830

Princess Margaret Cancer Center, University Health Network, 101 College Street, Toronto, ON M5G 1L7, Canada; Department of Medical Biophysics, University of Toronto, 101 College Street, Toronto, ON M5G 1L7, Canada; Department of Radiation Oncology, University of Toronto, 149 College Street, Toronto, ON M5T 1P5, Canada. Electronic address:

The kinetics of circulating cell-free DNA (cfDNA) release may provide a real-time assessment of induced cell death. However, there is a limited understanding of the underlying biological rationale for cfDNA release following distinct treatments and cell death mechanisms. Here, we uncover a complex interplay between apoptosis, necrosis, and senescence in determining cfDNA release kinetics. Read More

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http://dx.doi.org/10.1016/j.celrep.2020.107830DOI Listing

Opposing Ventral Striatal Medium Spiny Neuron Activities Shaped by Striatal Parvalbumin-Expressing Interneurons during Goal-Directed Behaviors.

Cell Rep 2020 Jun;31(13):107829

Department of Neuropsychiatry, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan. Electronic address:

Medium spiny neurons (MSNs) of mice show opposing activities upon the initiation of a food-seeking lever press task. Ventromedial striatal (VMS)-MSNs are inhibited but ventrolateral striatal (VLS)-MSNs are activated; these activities mediate action selection and action initiation, respectively. To understand what input shapes the opposing MSN activities, here, we monitor cortical input activities at the cell population level and artificially reverse them. Read More

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http://dx.doi.org/10.1016/j.celrep.2020.107829DOI Listing

Angiocrine Sphingosine-1-Phosphate Activation of S1PR2-YAP Signaling Axis in Alveolar Type II Cells Is Essential for Lung Repair.

Cell Rep 2020 Jun;31(13):107828

Department of Pharmacology and Regenerative Medicine, University of Illinois College of Medicine, Chicago, IL 60612, USA. Electronic address:

Lung alveolar epithelium is composed of alveolar type I (AT1) and type II (AT2) cells. AT1 cells mediate gas exchange, whereas AT2 cells act as progenitor cells to repair injured alveoli. Lung microvascular endothelial cells (LMVECs) play a crucial but still poorly understood role in regulating alveolar repair. Read More

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http://dx.doi.org/10.1016/j.celrep.2020.107828DOI Listing

The PD-1 Pathway Regulates Development and Function of Memory CD8 T Cells following Respiratory Viral Infection.

Cell Rep 2020 Jun;31(13):107827

Department of Immunology, Blavatnik Institute, Harvard Medical School, and Evergrande Center for Immunologic Diseases, Harvard Medical School and Brigham and Women's Hospital, Boston, MA 02115, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Department of Pathology, Brigham and Women's Hospital, Boston, MA 02115, USA. Electronic address:

The PD-1 pathway regulates dysfunctional T cells in chronic infection and cancer, but the role of this pathway during acute infection remains less clear. Here, we demonstrate that PD-1 signals are needed for optimal memory. Mice deficient in the PD-1 pathway exhibit impaired CD8 T cell memory following acute influenza infection, including reduced virus-specific CD8 T cell numbers and compromised recall responses. Read More

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http://dx.doi.org/10.1016/j.celrep.2020.107827DOI Listing

The AP1 Transcription Factor Fosl2 Promotes Systemic Autoimmunity and Inflammation by Repressing Treg Development.

Cell Rep 2020 Jun;31(13):107826

Center of Experimental Rheumatology, Department of Rheumatology, University Hospital Zurich, Zurich, Switzerland; Faculty of Medicine, University of Zurich, Zurich, Switzerland. Electronic address:

Regulatory T cells (Tregs) represent a major population in the control of immune homeostasis and autoimmunity. Here we show that Fos-like 2 (Fosl2), a TCR-induced AP1 transcription factor, represses Treg development and controls autoimmunity. Mice overexpressing Fosl2 (Fosl2) indeed show a systemic inflammatory phenotype, with immune infiltrates in multiple organs. Read More

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http://dx.doi.org/10.1016/j.celrep.2020.107826DOI Listing

Counter Regulation of Spic by NF-κB and STAT Signaling Controls Inflammation and Iron Metabolism in Macrophages.

Cell Rep 2020 Jun;31(13):107825

Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, PA 19104, USA; Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, PA 19104, USA; Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, PA 19104, USA. Electronic address:

Activated macrophages must carefully calibrate their inflammatory responses to balance efficient pathogen control with inflammation-mediated tissue damage, but the molecular underpinnings of this "balancing act" remain unclear. Using genetically engineered mouse models and primary macrophage cultures, we show that Toll-like receptor (TLR) signaling induces the expression of the transcription factor Spic selectively in patrolling monocytes and tissue macrophages by a nuclear factor κB (NF-κB)-dependent mechanism. Functionally, Spic downregulates pro-inflammatory cytokines and promotes iron efflux by regulating ferroportin expression in activated macrophages. Read More

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http://dx.doi.org/10.1016/j.celrep.2020.107825DOI Listing

Zygotic Nuclear F-Actin Safeguards Embryonic Development.

Cell Rep 2020 Jun;31(13):107824

Graduate School of Biology-Oriented Science and Technology, Kindai University, Kinokawa-shi, Wakayama 649-6493, Japan. Electronic address:

After fertilization, sperm and oocyte nuclei are rapidly remodeled to form swollen pronuclei (PN) in mammalian zygotes, and the proper formation and function of PN are key to producing totipotent zygotes. However, how mature PN are formed has been unclear. We find that filamentous actin (F-actin) assembles in the PN of mouse zygotes and is required for fully functional PN. Read More

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http://dx.doi.org/10.1016/j.celrep.2020.107824DOI Listing

Mapping of Influenza Virus RNA-RNA Interactions Reveals a Flexible Network.

Cell Rep 2020 Jun;31(13):107823

Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, 450 Technology Drive, Pittsburgh, PA 15219, USA. Electronic address:

Selective assembly of influenza virus segments into virions is proposed to be mediated through intersegmental RNA-RNA interactions. Here, we developed a method called 2CIMPL that includes proximity ligation under native conditions to identify genome-wide RNA duplexes. Interactions between all eight segments were observed at multiple sites along a given segment and are concentrated at hotspots. Read More

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http://dx.doi.org/10.1016/j.celrep.2020.107823DOI Listing

T Cell-Intrinsic IRF5 Regulates T Cell Signaling, Migration, and Differentiation and Promotes Intestinal Inflammation.

Cell Rep 2020 Jun;31(13):107820

Department of Internal Medicine, Yale University, New Haven, CT, USA. Electronic address:

IRF5 polymorphisms are associated with multiple immune-mediated diseases, including ulcerative colitis. IRF5 contributions are attributed to its role in myeloid lineages. How T cell-intrinsic IRF5 contributes to inflammatory outcomes is not well understood. Read More

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http://dx.doi.org/10.1016/j.celrep.2020.107820DOI Listing

Control of Early B Cell Development by the RNA N-Methyladenosine Methylation.

Cell Rep 2020 Jun;31(13):107819

Department of Medicine, Section of Rheumatology and Gwen Knapp Center for Lupus and Immunology Research, The University of Chicago, Chicago, IL 60637, USA; Committee on Immunology, The University of Chicago, Chicago, IL 60637, USA. Electronic address:

The RNA N-methyladenosine (mA) methylation is installed by the METTL3-METTL14 methyltransferase complex. This modification has critical regulatory roles in various biological processes. Here, we report that deletion of Mettl14 dramatically reduces mRNA mA methylation in developing B cells and severely blocks B cell development in mice. Read More

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http://dx.doi.org/10.1016/j.celrep.2020.107819DOI Listing

Adipocyte-Derived Versican and Macrophage-Derived Biglycan Control Adipose Tissue Inflammation in Obesity.

Cell Rep 2020 Jun;31(13):107818

Department of Medicine, Division of Metabolism, Endocrinology, and Nutrition, University of Washington, Seattle, WA, USA. Electronic address:

Obesity is characterized by adipose tissue inflammation. Because proteoglycans regulate inflammation, here we investigate their role in adipose tissue inflammation in obesity. We find that adipose tissue versican and biglycan increase in obesity. Read More

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http://dx.doi.org/10.1016/j.celrep.2020.107818DOI Listing

Widespread Inhibition, Antagonism, and Synergy in Mouse Olfactory Sensory Neurons In Vivo.

Cell Rep 2020 Jun;31(13):107814

Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan; Laboratory for Sensory Circuit Formation, RIKEN Center for Developmental Biology, Kobe 650-0047, Japan. Electronic address:

Sensory information is selectively or non-selectively enhanced and inhibited in the brain, but it remains unclear whether and how this occurs at the most peripheral level. Using in vivo calcium imaging of mouse olfactory bulb and olfactory epithelium in wild-type and mutant animals, we show that odors produce not only excitatory but also inhibitory responses in olfactory sensory neurons (OSNs). Heterologous assays indicate that odorants can act as agonists to some but inverse agonists to other odorant receptors. Read More

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http://dx.doi.org/10.1016/j.celrep.2020.107814DOI Listing

H1N1 Influenza Virus Cross-Activates Gli1 to Disrupt the Intercellular Junctions of Alveolar Epithelial Cells.

Cell Rep 2020 Jun;31(13):107801

College of Veterinary Medicine, Yangzhou University, Yangzhou 225009, Jiangsu Province, PRC; Institute of Comparative Medicine, Yangzhou University, Yangzhou 225009, Jiangsu Province, PRC; Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonosis, Yangzhou University, Yangzhou 225009, Jiangsu Province, PRC; Institutes of Agricultural Science and Technology Development, Yangzhou University, Joint International Research Laboratory of Agriculture and Agri-Product Safety of Ministry of Education of China, Yangzhou University, Yangzhou 225009, Jiangsu Province, PRC. Electronic address:

Influenza A virus (IAV) primarily infects the airway and alveolar epithelial cells and disrupts the intercellular junctions, leading to increased paracellular permeability. Although this pathological change plays a critical role in lung tissue injury and secondary infection, the molecular mechanism of IAV-induced damage to the alveolar barrier remains obscure. Here, we report that Gli1, a transcription factor in the sonic hedgehog (Shh) signaling pathway, is cross-activated by the MAP and PI3 kinase pathways in H1N1 virus (PR8)-infected A549 cells and in the lungs of H1N1 virus-infected mice. Read More

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http://dx.doi.org/10.1016/j.celrep.2020.107801DOI Listing

The Leucine-Rich Repeat Region of CARMIL1 Regulates IL-1-Mediated ERK Activation, MMP Expression, and Collagen Degradation.

Cell Rep 2020 Jun;31(13):107781

Faculty of Dentistry, University of Toronto, Toronto, ON M5G 1G6, Canada; Division of Pulmonary, Critical Care & Sleep Medicine, Department of Medicine, National Jewish Health, Denver, CO 80206, USA. Electronic address:

CARMILs are large, multidomain, membrane-associated proteins that regulate actin assembly and Rho-family GTPases, but their role in inflammatory signaling is not defined. Tandem mass tag mass spectrometry indicated that, in fibroblasts, CARMIL1 associates with interleukin (IL)-1 signaling molecules. Immunoprecipitation of cells transfected with CARMIL1 mutants showed that the leucine-rich repeat (LRR) region of CARMIL1 associates with IL-1 receptor type 1 (IL-1R1) and IL-1 receptor-associated kinase (IRAK). Read More

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http://dx.doi.org/10.1016/j.celrep.2020.107781DOI Listing

Critical Role of Type III Interferon in Controlling SARS-CoV-2 Infection in Human Intestinal Epithelial Cells.

Cell Rep 2020 Jun 19:107863. Epub 2020 Jun 19.

Research Group "Cellular polarity and viral infection," German Cancer Research Center (DKFZ), Heidelberg 69120, Germany; Department of Infectious Diseases, Virology, Heidelberg University, Heidelberg 69120, Germany. Electronic address:

Severe acute respiratory syndrome-related coronavirus-2 (SARS-CoV-2) is an unprecedented worldwide health problem that requires concerted and global approaches to stop the coronavirus 2019 (COVID-19) pandemic. Although SARS-CoV-2 primarily targets lung epithelium cells, there is growing evidence that the intestinal epithelium is also infected. Here, using both colon-derived cell lines and primary non-transformed colon organoids, we engage in the first comprehensive analysis of the SARS-CoV-2 life cycle in human intestinal epithelial cells (hIECs). Read More

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http://dx.doi.org/10.1016/j.celrep.2020.107863DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7303637PMC

Phenotypic Screen with TSC-Deficient Neurons Reveals Heat-Shock Machinery as a Druggable Pathway for mTORC1 and Reduced Cilia.

Cell Rep 2020 Jun;31(12):107780

F.M. Kirby Neurobiology Center, Translational Neuroscience Center, Department of Neurology, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA. Electronic address:

Tuberous sclerosis complex (TSC) is a neurogenetic disorder that leads to elevated mechanistic targeting of rapamycin complex 1 (mTORC1) activity. Cilia can be affected by mTORC1 signaling, and ciliary deficits are associated with neurodevelopmental disorders. Here, we examine whether neuronal cilia are affected in TSC. Read More

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http://dx.doi.org/10.1016/j.celrep.2020.107780DOI Listing

Targeting Bim via a lncRNA Morrbid Regulates the Survival of Preleukemic and Leukemic Cells.

Cell Rep 2020 Jun;31(12):107816

Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN, USA; Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, IN, USA. Electronic address:

Inhibition of anti-apoptotic proteins BCL-2 and MCL-1 to release pro-apoptotic protein BIM and reactivate cell death could potentially be an efficient strategy for the treatment of leukemia. Here, we show that a lncRNA, MORRBID, a selective transcriptional repressor of BIM, is overexpressed in human acute myeloid leukemia (AML), which is associated with poor overall survival. In both human and animal models, MORRBID hyperactivation correlates with two recurrent AML drivers, TET2 and FLT3. Read More

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http://dx.doi.org/10.1016/j.celrep.2020.107816DOI Listing

CD28 Regulates Metabolic Fitness for Long-Lived Plasma Cell Survival.

Cell Rep 2020 Jun;31(12):107815

Department of Immunology, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA; Department of Medicine, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA. Electronic address:

Durable humoral immunity against epidemic infectious disease requires the survival of long-lived plasma cells (LLPCs). LLPC longevity is dependent on metabolic programs distinct from short-lived plasma cells (SLPCs); however, the mechanistic basis for this difference is unclear. We have previously shown that CD28, the prototypic T cell costimulatory receptor, is expressed on both LLPCs and SLPCs but is essential only for LLPC survival. Read More

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http://dx.doi.org/10.1016/j.celrep.2020.107815DOI Listing

A Family of T6SS Antibacterial Effectors Related to l,d-Transpeptidases Targets the Peptidoglycan.

Cell Rep 2020 Jun;31(12):107813

Departamento de Microbiologia, Instituto de Ciências Biomédicas, Universidade de São Paulo, São Paulo 05508-900, Brazil. Electronic address:

Type VI secretion systems (T6SSs) are nanomachines used by bacteria to inject toxic effectors into competitors. The identity and mechanism of many effectors remain unknown. We characterized a Salmonella T6SS antibacterial effector called Tlde1 that is toxic in target-cell periplasm and is neutralized by its cognate immunity protein (Tldi1). Read More

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http://dx.doi.org/10.1016/j.celrep.2020.107813DOI Listing

Dopamine Inputs from the Ventral Tegmental Area into the Medial Prefrontal Cortex Modulate Neuropathic Pain-Associated Behaviors in Mice.

Cell Rep 2020 Jun;31(12):107812

Department of Physiology and Pharmacology, Hotchkiss Brain Institute, Alberta Children's Hospital Research Institute, Cumming School of Medicine, University of Calgary, Calgary, AB T2N 4N1, Canada. Electronic address:

The medial prefrontal cortex (mPFC) is a brain region involved in the affective components of pain and undergoes plasticity during the development of chronic pain. Dopamine (DA) is a key neuromodulator in the mesocortical circuit and modulates working memory and aversion. Although DA inputs into the mPFC are known to modulate plasticity, whether and how these inputs affect pain remains incompletely understood. Read More

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http://dx.doi.org/10.1016/j.celrep.2020.107812DOI Listing

Site-Specific Incorporation of Two ncAAs for Two-Color Bioorthogonal Labeling and Crosslinking of Proteins on Live Mammalian Cells.

Cell Rep 2020 Jun;31(12):107811

Science for Life Laboratory, Karolinska Institutet, Department of Medical Biochemistry and Biophysics, Division of Genome Biology, Stockholm 17165, Sweden; Ming Wai Lau Centre for Reparative Medicine, Stockholm node, Karolinska Institutet, Stockholm 17165, Sweden. Electronic address:

The pyrrolysyl-tRNA/pyrrolysyl-tRNA synthetase (PylT/RS) pair from the archaeon Methanosarcina mazei (Mma) is widely used in protein engineering to site-specifically introduce noncanonical amino acids (ncAAs) through nonsense codon suppression. Here, we engineer the PylT/RS pair encoded by Methanogenic archaeon ISO4-G1 (G1) to be orthogonal to Mma PylT/RS and alter the G1 PylRS active site to accept a complementary ncAA spectrum. We combine the resulting mutual orthogonal pairs for site-specific dual ncAA incorporation of two lysine analogs with high selectivity and efficiency. Read More

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http://dx.doi.org/10.1016/j.celrep.2020.107811DOI Listing

mTOR Overcomes Multiple Metabolic Restrictions to Enable HIV-1 Reverse Transcription and Intracellular Transport.

Cell Rep 2020 Jun;31(12):107810

Division of Infectious Diseases and HIV Translational Research Center, Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA. Electronic address:

Cellular metabolism governs the susceptibility of CD4 T cells to HIV-1 infection. Multiple early post-fusion steps of HIV-1 replication are restricted in resting peripheral blood CD4 T cells; however, molecular mechanisms that underlie metabolic control of these steps remain undefined. Here, we show that mTOR activity following T cell stimulatory signals overcomes metabolic restrictions in these cells by enabling the expansion of dNTPs to fuel HIV-1 reverse transcription (RT), as well as increasing acetyl-CoA to stabilize microtubules that transport RT products. Read More

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http://dx.doi.org/10.1016/j.celrep.2020.107810DOI Listing

Small Molecule Dysregulation of TEAD Lipidation Induces a Dominant-Negative Inhibition of Hippo Pathway Signaling.

Cell Rep 2020 Jun;31(12):107809

Department of Early Discovery Biochemistry, Genentech, South San Francisco, CA 94080, USA. Electronic address:

The transcriptional enhanced associate domain (TEAD) family of transcription factors serves as the receptors for the downstream effectors of the Hippo pathway, YAP and TAZ, to upregulate the expression of multiple genes involved in cellular proliferation and survival. Recent work identified TEAD S-palmitoylation as critical for protein stability and activity as the lipid tail extends into a hydrophobic core of the protein. Here, we report the identification and characterization of a potent small molecule that binds the TEAD lipid pocket (LP) and disrupts TEAD S-palmitoylation. Read More

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http://dx.doi.org/10.1016/j.celrep.2020.107809DOI Listing

Skeletal Muscle Transcriptomic Comparison between Long-Term Trained and Untrained Men and Women.

Cell Rep 2020 Jun;31(12):107808

Department of Physiology and Pharmacology, Karolinska Institutet, 171 77 Stockholm, Sweden; Department of Learning, Informatics, Management and Ethics, Karolinska Institutet, 171 77 Stockholm, Sweden; Department of Laboratory Medicine, Karolinska Institutet, 141 52 Huddinge, Sweden.

To better understand the health benefits of lifelong exercise in humans, we conduct global skeletal muscle transcriptomic analyses of long-term endurance- (9 men, 9 women) and strength-trained (7 men) humans compared with age-matched untrained controls (7 men, 8 women). Transcriptomic analysis, Gene Ontology, and genome-scale metabolic modeling demonstrate changes in pathways related to the prevention of metabolic diseases, particularly with endurance training. Our data also show prominent sex differences between controls and that these differences are reduced with endurance training. Read More

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http://dx.doi.org/10.1016/j.celrep.2020.107808DOI Listing

Identification of Conserved Proteomic Networks in Neurodegenerative Dementia.

Cell Rep 2020 Jun;31(12):107807

Program in Neurogenetics, Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA; Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA; Institute of Precision Health, University of California, Los Angeles, Los Angeles, CA 90095, USA. Electronic address:

Data-driven analyses are increasingly valued in modern medicine. We integrate quantitative proteomics and transcriptomics from over 1,000 post-mortem brains from six cohorts representing Alzheimer's disease (AD), asymptomatic AD, progressive supranuclear palsy (PSP), and control patients from the Accelerating Medicines Partnership - Alzheimer's Disease consortium. We define robust co-expression trajectories related to disease progression, including early neuronal, microglial, astrocyte, and immune response modules, and later mRNA splicing and mitochondrial modules. Read More

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http://dx.doi.org/10.1016/j.celrep.2020.107807DOI Listing

mTOR Signaling and SREBP Activity Increase FADS2 Expression and Can Activate Sapienate Biosynthesis.

Cell Rep 2020 Jun;31(12):107806

Laboratory of Cellular Metabolism and Metabolic Regulation, VIB-KU Leuven Center for Cancer Biology, VIB, Herestraat 49, 3000 Leuven, Belgium; Laboratory of Cellular Metabolism and Metabolic Regulation, Department of Oncology, KU Leuven and Leuven Cancer Institute (LKI), Herestraat 49, 3000 Leuven, Belgium. Electronic address:

Cancer cells display an increased plasticity in their lipid metabolism, which includes the conversion of palmitate to sapienate via the enzyme fatty acid desaturase 2 (FADS2). We find that FADS2 expression correlates with mammalian target of rapamycin (mTOR) signaling and sterol regulatory element-binding protein 1 (SREBP-1) activity across multiple cancer types and is prognostic in some cancer types. Accordingly, activating mTOR signaling by deleting tuberous sclerosis complex 2 (Tsc2) or overexpression of SREBP-1/2 is sufficient to increase FADS2 mRNA expression and sapienate metabolism in mouse embryonic fibroblasts (MEFs) and U87 glioblastoma cells, respectively. Read More

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http://dx.doi.org/10.1016/j.celrep.2020.107806DOI Listing

Single-Cell Profiling and SCOPE-Seq Reveal Lineage Dynamics of Adult Ventricular-Subventricular Zone Neurogenesis and NOTUM as a Key Regulator.

Cell Rep 2020 Jun;31(12):107805

Department of Systems Biology, Columbia University Irving Medical Center, New York, NY 10032, USA; Department of Biochemistry & Molecular Biophysics, Columbia University Irving Medical Center, New York, NY 10032, USA. Electronic address:

In the adult ventricular-subventricular zone (V-SVZ), neural stem cells (NSCs) generate new olfactory bulb (OB) neurons and glia throughout life. To map adult neuronal lineage progression, we profiled >56,000 V-SVZ and OB cells by single-cell RNA sequencing (scRNA-seq). Our analyses reveal the molecular diversity of OB neurons, including fate-mapped neurons, lineage progression dynamics, and an NSC intermediate enriched for Notum, which encodes a secreted WNT antagonist. Read More

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http://dx.doi.org/10.1016/j.celrep.2020.107805DOI Listing

Resolving Cell Cycle Speed in One Snapshot with a Live-Cell Fluorescent Reporter.

Cell Rep 2020 Jun;31(12):107804

Department of Cell Biology, Yale University, New Haven, CT 06520, USA; Yale Stem Cell Center, Yale University, New Haven, CT 06520, USA. Electronic address:

Cell proliferation changes concomitantly with fate transitions during reprogramming, differentiation, regeneration, and oncogenesis. Methods to resolve cell cycle length heterogeneity in real time are currently lacking. Here, we describe a genetically encoded fluorescent reporter that captures live-cell cycle speed using a single measurement. Read More

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http://dx.doi.org/10.1016/j.celrep.2020.107804DOI Listing

Enhancer RNAs Mediate Estrogen-Induced Decommissioning of Selective Enhancers by Recruiting ERα and Its Cofactor.

Cell Rep 2020 Jun;31(12):107803

Department of Molecular Medicine, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA. Electronic address:

The function of enhancer RNAs (eRNAs) in transcriptional regulation remains obscure. By analyzing the genome-wide nascent transcript profiles in breast cancer cells, we identify a special group of eRNAs that are essential for estrogen-induced transcriptional repression. Using eRNAs of TM4SF1 and EFEMP1 as the paradigms, we find that these RNA molecules not only stabilize promoter-enhancer interactions but also recruit liganded estrogen receptor α (ERα) to particular enhancer regions, facilitate the formation of a functional transcriptional complex, and cause gene silencing. Read More

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http://dx.doi.org/10.1016/j.celrep.2020.107803DOI Listing

Fibroblast-Derived STC-1 Modulates Tumor-Associated Macrophages and Lung Adenocarcinoma Development.

Cell Rep 2020 Jun;31(12):107802

Leicester Cancer Research Centre, University of Leicester, Leicester Royal Infirmary, Leicester LE2 7LX, UK. Electronic address:

The tumor microenvironment (TME) consists of different cell types, including tumor-associated macrophages (TAMs) and tumor-associated fibroblasts (TAFs). How these cells interact and contribute to lung carcinogenesis remains elusive. Using KRAS- and BRAF-driven mouse lung models, we identify the pleiotropic glycoprotein stanniocalcin-1 (STC1) as a regulator of TAM-TAF interactions. Read More

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http://dx.doi.org/10.1016/j.celrep.2020.107802DOI Listing

Drug GRADE: An Integrated Analysis of Population Growth and Cell Death Reveals Drug-Specific and Cancer Subtype-Specific Response Profiles.

Cell Rep 2020 Jun;31(12):107800

Program in Systems Biology (PSB), University of Massachusetts Medical School, Worcester, MA, USA; Program in Molecular Medicine (PMM), Department of Molecular, Cell, and Cancer Biology (MCCB), University of Massachusetts Medical School, Worcester, MA, USA. Electronic address:

When evaluating anti-cancer drugs, two different measurements are used: relative viability, which scores an amalgam of proliferative arrest and cell death, and fractional viability, which specifically scores the degree of cell killing. We quantify relationships between drug-induced growth inhibition and cell death by counting live and dead cells using quantitative microscopy. We find that most drugs affect both proliferation and death, but in different proportions and with different relative timing. Read More

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http://dx.doi.org/10.1016/j.celrep.2020.107800DOI Listing

Recently Evolved Enhancers Emerge with High Interindividual Variability and Less Frequently Associate with Disease.

Cell Rep 2020 Jun;31(12):107799

Hubrecht Institute-KNAW & University Medical Center Utrecht, Utrecht, the Netherlands; Erasmus University Medical Center, Department of Developmental Biology, Wytemaweg 80, 3015 CN Rotterdam, the Netherlands. Electronic address:

Mutations in non-coding regulatory DNA such as enhancers underlie a wide variety of diseases including developmental disorders and cancer. As enhancers rapidly evolve, understanding their function and configuration in non-human disease models can have important clinical applications. Here, we analyze enhancer configurations in tissues isolated from the common marmoset, a widely used primate model for human disease. Read More

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http://dx.doi.org/10.1016/j.celrep.2020.107799DOI Listing

Stabilization of Endothelial Receptor Arrays by a Polarized Spectrin Cytoskeleton Facilitates Rolling and Adhesion of Leukocytes.

Cell Rep 2020 Jun;31(12):107798

Program in Cell Biology, Peter Gilgan Centre for Research and Learning, Hospital for Sick Children, 686 Bay Street, 19-9800, Toronto, ON M5G 0A4, Canada; Department of Biochemistry, University of Toronto, 1 King's College Circle, Toronto, ON M5S 1A8, Canada. Electronic address:

Multivalent complexes of endothelial adhesion receptors (e.g., selectins) engage leukocytes to orchestrate their migration to inflamed tissues. Read More

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http://dx.doi.org/10.1016/j.celrep.2020.107798DOI Listing

Tonic GABAergic Inhibition Is Essential for Nerve Injury-Induced Afferent Remodeling in the Somatosensory Thalamus and Ectopic Sensations.

Cell Rep 2020 Jun;31(12):107797

Department of Physiology, Division of Neurophysiology, School of Medicine, Tokyo Women's Medical University, Tokyo 162-8666, Japan. Electronic address:

Peripheral nerve injury induces functional and structural remodeling of neural circuits along the somatosensory pathways, forming the basis for somatotopic reorganization and ectopic sensations, such as referred phantom pain. However, the mechanisms underlying that remodeling remain largely unknown. Whisker sensory nerve injury drives functional remodeling in the somatosensory thalamus: the number of afferent inputs to each thalamic neuron increases from one to many. Read More

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http://dx.doi.org/10.1016/j.celrep.2020.107797DOI Listing