19,879 results match your criteria Cell[Journal]


Protein Sequence Editing of SKN-1A/Nrf1 by Peptide:N-Glycanase Controls Proteasome Gene Expression.

Cell 2019 Apr;177(3):737-750.e15

Department of Molecular Biology, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Genetics, Harvard Medical School, Boston, MA 02115, USA. Electronic address:

The proteasome mediates selective protein degradation and is dynamically regulated in response to proteotoxic challenges. SKN-1A/Nrf1, an endoplasmic reticulum (ER)-associated transcription factor that undergoes N-linked glycosylation, serves as a sensor of proteasome dysfunction and triggers compensatory upregulation of proteasome subunit genes. Here, we show that the PNG-1/NGLY1 peptide:N-glycanase edits the sequence of SKN-1A protein by converting particular N-glycosylated asparagine residues to aspartic acid. Read More

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http://dx.doi.org/10.1016/j.cell.2019.03.035DOI Listing

SIRT6 Is Responsible for More Efficient DNA Double-Strand Break Repair in Long-Lived Species.

Cell 2019 Apr;177(3):622-638.e22

Department of Biology, University of Rochester, Rochester, NY 14627, USA. Electronic address:

DNA repair has been hypothesized to be a longevity determinant, but the evidence for it is based largely on accelerated aging phenotypes of DNA repair mutants. Here, using a panel of 18 rodent species with diverse lifespans, we show that more robust DNA double-strand break (DSB) repair, but not nucleotide excision repair (NER), coevolves with longevity. Evolution of NER, unlike DSB, is shaped primarily by sunlight exposure. Read More

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http://dx.doi.org/10.1016/j.cell.2019.03.043DOI Listing

Human Gain-of-Function MC4R Variants Show Signaling Bias and Protect against Obesity.

Cell 2019 Apr;177(3):597-607.e9

University of Cambridge Metabolic Research Laboratories and NIHR Cambridge Biomedical Research Centre, Wellcome Trust-MRC Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge CB2 0QQ, UK. Electronic address:

The melanocortin 4 receptor (MC4R) is a G protein-coupled receptor whose disruption causes obesity. We functionally characterized 61 MC4R variants identified in 0.5 million people from UK Biobank and examined their associations with body mass index (BMI) and obesity-related cardiometabolic diseases. Read More

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http://dx.doi.org/10.1016/j.cell.2019.03.044DOI Listing

Polygenic Prediction of Weight and Obesity Trajectories from Birth to Adulthood.

Cell 2019 Apr;177(3):587-596.e9

Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA 02114, USA; Division of Cardiology, Massachusetts General Hospital, Boston, MA 02114, USA; Cardiovascular Disease Initiative, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Department of Medicine, Harvard Medical School, Boston, MA 02115, USA. Electronic address:

Severe obesity is a rapidly growing global health threat. Although often attributed to unhealthy lifestyle choices or environmental factors, obesity is known to be heritable and highly polygenic; the majority of inherited susceptibility is related to the cumulative effect of many common DNA variants. Here we derive and validate a new polygenic predictor comprised of 2. Read More

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https://linkinghub.elsevier.com/retrieve/pii/S00928674193029
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http://dx.doi.org/10.1016/j.cell.2019.03.028DOI Listing
April 2019
1 Read

B Cell Responses: Cell Interaction Dynamics and Decisions.

Cell 2019 Apr;177(3):524-540

Cardiovascular Research Institute, Department of Anatomy, and Sandler Asthma Basic Research Center, University of California, San Francisco, San Francisco, CA 94143, USA. Electronic address:

B cells and the antibodies they produce have a deeply penetrating influence on human physiology. Here, we review current understanding of how B cell responses are initiated; the different paths to generate short- and long-lived plasma cells, germinal center cells, and memory cells; and how each path impacts antibody diversity, selectivity, and affinity. We discuss how basic research is informing efforts to generate vaccines that induce broadly neutralizing antibodies against viral pathogens, revealing the special features associated with allergen-reactive IgE responses and uncovering the antibody-independent mechanisms by which B cells contribute to health and disease. Read More

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https://linkinghub.elsevier.com/retrieve/pii/S00928674193027
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http://dx.doi.org/10.1016/j.cell.2019.03.016DOI Listing
April 2019
1 Read

The Least Mating Pathway: Synthetically Refactoring a Familiar Signaling System for New Applications.

Cell 2019 Apr;177(3):521-523

Department of Bioengineering, Rice University, Houston, TX 77030, USA; Department of Biosciences, Rice University, Houston, TX 77030, USA. Electronic address:

Synthetic refactoring makes naturally occurring regulatory systems more amenable to manipulation by removing or recoding their natural genetic complexity. Shaw et al. apply this technique to the yeast mating response pathway, creating a simplified, highly engineerable signaling module that can be used to construct precisely optimized, application-specific GPCR biosensors. Read More

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http://dx.doi.org/10.1016/j.cell.2019.04.003DOI Listing

Polygenic Risk Scores Expand to Obesity.

Cell 2019 Apr;177(3):518-520

Scripps Research Translational Institute, La Jolla, CA 92037, USA; Department of Molecular Medicine, Scripps Research, La Jolla, CA 92037, USA. Electronic address:

Obesity is one of the most serious health challenges of our time. In this issue of Cell, Khera and co-authors demonstrate the striking ability of genetics, in the form of a polygenic risk score, to identify those individuals at high risk for obesity. This genetic risk expresses itself early as childhood obesity, reinforcing the notion that early prevention is essential to combatting the obesity epidemic. Read More

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http://dx.doi.org/10.1016/j.cell.2019.03.051DOI Listing

Hear Pancreatic Cancer Stem Cells ROR.

Cell 2019 Apr;177(3):516-518

Department of Translational Molecular Pathology and Sheikh Ahmed Center for Pancreatic Cancer Research, University of Texas M.D. Anderson Cancer Center, Houston, TX, USA.

In this issue of Cell, Lytle et al. (2019) integrate functional genomic approaches to identify molecular dependencies of pancreatic cancer stem cells that may be exploited therapeutically. The comprehensive analysis reveals an unexpected role for retinoic acid receptor-related orphan receptor gamma (RORγ), a T-cell-associated transcription factor, in defining the stemness and the aggressive behavior of pancreatic cancer. Read More

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https://linkinghub.elsevier.com/retrieve/pii/S00928674193038
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http://dx.doi.org/10.1016/j.cell.2019.04.002DOI Listing
April 2019
1 Read

"Cloaking" on Time: A Cover-Up Act by Resident Tissue Macrophages.

Cell 2019 Apr;177(3):514-516

Singapore Immunology Network (SIgN), Agency for Science, Technology and Research (A∗STAR), 8A Biomedical Grove, Immunos Building #3-4, Biopolis, Singapore 138648, Singapore; Shanghai Institute of Immunology, Shanghai JiaoTong University School of Medicine, 280 South Chongqing Road, Shanghai 200025, China. Electronic address:

In this issue of Cell, Uderhardt et al. employed intravital two-photon microscopy to examine tissue-resident macrophage responses to sterile cellular injuries of variable size. They observed that while multi-cell "macrolesions" are characteristically pro-inflammatory, resident macrophages can "cloak" single-cell microlesions to prevent excessive neutrophil recruitment and limit subsequent tissue damage. Read More

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http://dx.doi.org/10.1016/j.cell.2019.03.042DOI Listing

Redox State Controls Phase Separation of the Yeast Ataxin-2 Protein via Reversible Oxidation of Its Methionine-Rich Low-Complexity Domain.

Cell 2019 Apr 11;177(3):711-721.e8. Epub 2019 Apr 11.

Department of Biochemistry, UT Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390-9038, USA. Electronic address:

Yeast ataxin-2, also known as Pbp1, senses the activity state of mitochondria in order to regulate TORC1. A domain of Pbp1 required to adapt cells to mitochondrial activity is of low sequence complexity. The low-complexity (LC) domain of Pbp1 forms labile, cross-β polymers that facilitate phase transition of the protein into liquid-like or gel-like states. Read More

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http://dx.doi.org/10.1016/j.cell.2019.02.044DOI Listing

A Compendium of Mutational Signatures of Environmental Agents.

Cell 2019 Apr 10. Epub 2019 Apr 10.

Academic Department of Medical Genetics, School of Clinical Medicine, University of Cambridge, Cambridge CB2 9NB, UK; MRC Cancer Unit, University of Cambridge, Cambridge CB2 0XZ, UK; Wellcome Trust Sanger Institute, Hinxton CB10 1SA, UK. Electronic address:

Whole-genome-sequencing (WGS) of human tumors has revealed distinct mutation patterns that hint at the causative origins of cancer. We examined mutational signatures in 324 WGS human-induced pluripotent stem cells exposed to 79 known or suspected environmental carcinogens. Forty-one yielded characteristic substitution mutational signatures. Read More

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https://linkinghub.elsevier.com/retrieve/pii/S00928674193026
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http://dx.doi.org/10.1016/j.cell.2019.03.001DOI Listing
April 2019
1 Read

Self-Organized Nuclear Positioning Synchronizes the Cell Cycle in Drosophila Embryos.

Cell 2019 Apr 9. Epub 2019 Apr 9.

Department of Cell Biology, Duke University Medical Center, Durham, NC 27710, USA. Electronic address:

The synchronous cleavage divisions of early embryogenesis require coordination of the cell-cycle oscillator, the dynamics of the cytoskeleton, and the cytoplasm. Yet, it remains unclear how spatially restricted biochemical signals are integrated with physical properties of the embryo to generate collective dynamics. Here, we show that synchronization of the cell cycle in Drosophila embryos requires accurate nuclear positioning, which is regulated by the cell-cycle oscillator through cortical contractility and cytoplasmic flows. Read More

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http://dx.doi.org/10.1016/j.cell.2019.03.007DOI Listing

Yeast Ataxin-2 Forms an Intracellular Condensate Required for the Inhibition of TORC1 Signaling during Respiratory Growth.

Cell 2019 Apr 11;177(3):697-710.e17. Epub 2019 Apr 11.

Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA. Electronic address:

Yeast ataxin-2, also known as Pbp1 (polyA binding protein-binding protein 1), is an intrinsically disordered protein implicated in stress granule formation, RNA biology, and neurodegenerative disease. To understand the endogenous function of this protein, we identify Pbp1 as a dedicated regulator of TORC1 signaling and autophagy under conditions that require mitochondrial respiration. Pbp1 binds to TORC1 specifically during respiratory growth, but utilizes an additional methionine-rich, low complexity (LC) region to inhibit TORC1. Read More

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http://dx.doi.org/10.1016/j.cell.2019.02.043DOI Listing

Primate Amygdala Neurons Simulate Decision Processes of Social Partners.

Cell 2019 Apr 10. Epub 2019 Apr 10.

Department of Physiology, Development and Neuroscience, University of Cambridge, Downing Street, Cambridge CB2 3DY, UK.

By observing their social partners, primates learn about reward values of objects. Here, we show that monkeys' amygdala neurons derive object values from observation and use these values to simulate a partner monkey's decision process. While monkeys alternated making reward-based choices, amygdala neurons encoded object-specific values learned from observation. Read More

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https://linkinghub.elsevier.com/retrieve/pii/S00928674193022
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http://dx.doi.org/10.1016/j.cell.2019.02.042DOI Listing
April 2019
6 Reads

A Single-Cell Atlas of the Tumor and Immune Ecosystem of Human Breast Cancer.

Cell 2019 Apr 10. Epub 2019 Apr 10.

Institute of Molecular Life Sciences, University of Zurich, Winterthurerstrasse 190, 8057 Zurich, Switzerland. Electronic address:

Breast cancer is a heterogeneous disease. Tumor cells and associated healthy cells form ecosystems that determine disease progression and response to therapy. To characterize features of breast cancer ecosystems and their associations with clinical data, we analyzed 144 human breast tumor and 50 non-tumor tissue samples using mass cytometry. Read More

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https://linkinghub.elsevier.com/retrieve/pii/S00928674193026
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http://dx.doi.org/10.1016/j.cell.2019.03.005DOI Listing
April 2019
5 Reads

Promoter-Intrinsic and Local Chromatin Features Determine Gene Repression in LADs.

Cell 2019 Apr 8. Epub 2019 Apr 8.

Division of Gene Regulation and Oncode Institute, Netherlands Cancer Institute, Amsterdam, the Netherlands. Electronic address:

It is largely unclear whether genes that are naturally embedded in lamina-associated domains (LADs) are inactive due to their chromatin environment or whether LADs are merely secondary to the lack of transcription. We show that hundreds of human promoters become active when moved from their native LAD position to a neutral context in the same cells, indicating that LADs form a repressive environment. Another set of promoters inside LADs is able to "escape" repression, although their transcription elongation is attenuated. Read More

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http://dx.doi.org/10.1016/j.cell.2019.03.009DOI Listing

Volumetric Ca Imaging in the Mouse Brain Using Hybrid Multiplexed Sculpted Light Microscopy.

Cell 2019 Apr 8. Epub 2019 Apr 8.

Laboratory of Neurotechnology and Biophysics, The Rockefeller University, New York, NY, USA; Research Institute of Molecular Pathology, Vienna, Austria; The Kavli Neural Systems Institute, The Rockefeller University, New York, NY, USA. Electronic address:

Calcium imaging using two-photon scanning microscopy has become an essential tool in neuroscience. However, in its typical implementation, the tradeoffs between fields of view, acquisition speeds, and depth restrictions in scattering brain tissue pose severe limitations. Here, using an integrated systems-wide optimization approach combined with multiple technical innovations, we introduce a new design paradigm for optical microscopy based on maximizing biological information while maintaining the fidelity of obtained neuron signals. Read More

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http://dx.doi.org/10.1016/j.cell.2019.03.011DOI Listing

Human Pluripotency Is Initiated and Preserved by a Unique Subset of Founder Cells.

Cell 2019 Apr 9. Epub 2019 Apr 9.

Stem Cell and Cancer Research Institute, McMaster University, Hamilton, ON L8S 4L8, Canada; Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, ON L8S 4L8, Canada. Electronic address:

The assembly of organized colonies is the earliest manifestation in the derivation or induction of pluripotency in vitro. However, the necessity and origin of this assemblance is unknown. Here, we identify human pluripotent founder cells (hPFCs) that initiate, as well as preserve and establish, pluripotent stem cell (PSC) cultures. Read More

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https://linkinghub.elsevier.com/retrieve/pii/S00928674193027
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http://dx.doi.org/10.1016/j.cell.2019.03.013DOI Listing
April 2019
1 Read

Multiple Deeply Divergent Denisovan Ancestries in Papuans.

Cell 2019 Apr 10. Epub 2019 Apr 10.

Statistics and Bioinformatics Group, School of Fundamental Sciences, Massey University, Palmerston North 4410, New Zealand. Electronic address:

Genome sequences are known for two archaic hominins-Neanderthals and Denisovans-which interbred with anatomically modern humans as they dispersed out of Africa. We identified high-confidence archaic haplotypes in 161 new genomes spanning 14 island groups in Island Southeast Asia and New Guinea and found large stretches of DNA that are inconsistent with a single introgressing Denisovan origin. Instead, modern Papuans carry hundreds of gene variants from two deeply divergent Denisovan lineages that separated over 350 thousand years ago. Read More

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http://dx.doi.org/10.1016/j.cell.2019.02.035DOI Listing

Engineering a Model Cell for Rational Tuning of GPCR Signaling.

Cell 2019 Apr 4;177(3):782-796.e27. Epub 2019 Apr 4.

Department of Bioengineering, Imperial College London, London SW7 2AZ, UK; Centre for Synthetic Biology, Imperial College London, London SW7 2AZ, UK. Electronic address:

G protein-coupled receptor (GPCR) signaling is the primary method eukaryotes use to respond to specific cues in their environment. However, the relationship between stimulus and response for each GPCR is difficult to predict due to diversity in natural signal transduction architecture and expression. Using genome engineering in yeast, we constructed an insulated, modular GPCR signal transduction system to study how the response to stimuli can be predictably tuned using synthetic tools. Read More

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http://dx.doi.org/10.1016/j.cell.2019.02.023DOI Listing

Somatic Mutations Increase Hepatic Clonal Fitness and Regeneration in Chronic Liver Disease.

Cell 2019 Apr 4;177(3):608-621.e12. Epub 2019 Apr 4.

Children's Research Institute, Departments of Pediatrics and Internal Medicine, Center for Regenerative Science and Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA. Electronic address:

Normal tissues accumulate genetic changes with age, but it is unknown if somatic mutations promote clonal expansion of non-malignant cells in the setting of chronic degenerative diseases. Exome sequencing of diseased liver samples from 82 patients revealed a complex mutational landscape in cirrhosis. Additional ultra-deep sequencing identified recurrent mutations in PKD1, PPARGC1B, KMT2D, and ARID1A. Read More

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http://dx.doi.org/10.1016/j.cell.2019.03.026DOI Listing
April 2019
2 Reads

Insulin Receptor Associates with Promoters Genome-wide and Regulates Gene Expression.

Cell 2019 Apr 4;177(3):722-736.e22. Epub 2019 Apr 4.

Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA; Program in Neuroscience, Harvard Medical School, Boston, MA 02115, USA. Electronic address:

Insulin receptor (IR) signaling is central to normal metabolic control and dysregulated in prevalent chronic diseases. IR binds insulin at the cell surface and transduces rapid signaling via cytoplasmic kinases. However, mechanisms mediating long-term effects of insulin remain unclear. Read More

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http://dx.doi.org/10.1016/j.cell.2019.02.030DOI Listing
April 2019
1 Read

A Jasmonate Signaling Network Activates Root Stem Cells and Promotes Regeneration.

Cell 2019 Apr 2. Epub 2019 Apr 2.

Laboratory of Plant Developmental Biology, Wageningen University and Research, 6708 PB Wageningen, the Netherlands; Rijk Zwaan R&D, 4793 RS Fijnaart, the Netherlands. Electronic address:

Plants are sessile and have to cope with environmentally induced damage through modification of growth and defense pathways. How tissue regeneration is triggered in such responses and whether this involves stem cell activation is an open question. The stress hormone jasmonate (JA) plays well-established roles in wounding and defense responses. Read More

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http://dx.doi.org/10.1016/j.cell.2019.03.006DOI Listing
April 2019
1 Read

Profiling of Pluripotency Factors in Single Cells and Early Embryos.

Cell 2019 Apr 2. Epub 2019 Apr 2.

Department of Molecular, Cell, and Cancer Biology, University of Massachusetts Medical School, Worcester, MA 01605, USA. Electronic address:

Cell fate decisions are governed by sequence-specific transcription factors (TFs) that act in small populations of cells within developing embryos. To understand their functions in vivo, it is important to identify TF binding sites in these cells. However, current methods cannot profile TFs genome-wide at or near the single-cell level. Read More

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http://dx.doi.org/10.1016/j.cell.2019.03.014DOI Listing

Resident Macrophages Cloak Tissue Microlesions to Prevent Neutrophil-Driven Inflammatory Damage.

Cell 2019 Apr 4;177(3):541-555.e17. Epub 2019 Apr 4.

Lymphocyte Biology Section, Laboratory of Immune System Biology, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, MD 20892, USA. Electronic address:

Neutrophils are attracted to and generate dense swarms at sites of cell damage in diverse tissues, often extending the local disruption of organ architecture produced by the initial insult. Whether the inflammatory damage resulting from such neutrophil accumulation is an inescapable consequence of parenchymal cell death has not been explored. Using a combination of dynamic intravital imaging and confocal multiplex microscopy, we report here that tissue-resident macrophages rapidly sense the death of individual cells and extend membrane processes that sequester the damage, a process that prevents initiation of the feedforward chemoattractant signaling cascade that results in neutrophil swarms. Read More

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http://dx.doi.org/10.1016/j.cell.2019.02.028DOI Listing

Genome-wide de novo L1 Retrotransposition Connects Endonuclease Activity with Replication.

Cell 2019 Apr 2. Epub 2019 Apr 2.

Department of Human Genetics, University of Michigan Medical School, Ann Arbor, Michigan, 48109, USA; Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan, 48109, USA. Electronic address:

L1 retrotransposon-derived sequences comprise approximately 17% of the human genome. Darwinian selective pressures alter L1 genomic distributions during evolution, confounding the ability to determine initial L1 integration preferences. Here, we generated high-confidence datasets of greater than 88,000 engineered L1 insertions in human cell lines that act as proxies for cells that accommodate retrotransposition in vivo. Read More

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http://dx.doi.org/10.1016/j.cell.2019.02.050DOI Listing

Antisense lncRNA Transcription Mediates DNA Demethylation to Drive Stochastic Protocadherin α Promoter Choice.

Cell 2019 Apr 4;177(3):639-653.e15. Epub 2019 Apr 4.

Department of Biochemistry and Molecular Biophysics, Columbia University, New York, NY 10032, USA; Mortimer B. Zuckerman Mind Brain and Behavior Institute, Columbia University, New York, NY 10027, USA; New York Genome Center, New York, NY 10013, USA. Electronic address:

Stochastic activation of clustered Protocadherin (Pcdh) α, β, and γ genes generates a cell-surface identity code in individual neurons that functions in neural circuit assembly. Here, we show that Pcdhα gene choice involves the activation of an antisense promoter located in the first exon of each Pcdhα alternate gene. Transcription of an antisense long noncoding RNA (lncRNA) from this antisense promoter extends through the sense promoter, leading to DNA demethylation of the CTCF binding sites proximal to each promoter. Read More

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http://dx.doi.org/10.1016/j.cell.2019.03.008DOI Listing
April 2019
1 Read
32.242 Impact Factor

A Multiscale Map of the Stem Cell State in Pancreatic Adenocarcinoma.

Cell 2019 Apr 4;177(3):572-586.e22. Epub 2019 Apr 4.

Department of Pharmacology, University of California, San Diego School of Medicine, La Jolla, CA, USA; Sanford Consortium for Regenerative Medicine, La Jolla, CA, USA; Moores Cancer Center, University of California, San Diego School of Medicine, La Jolla, CA, USA; Department of Medicine, University of California, San Diego School of Medicine, La Jolla, CA, USA. Electronic address:

Drug resistance and relapse remain key challenges in pancreatic cancer. Here, we have used RNA sequencing (RNA-seq), chromatin immunoprecipitation (ChIP)-seq, and genome-wide CRISPR analysis to map the molecular dependencies of pancreatic cancer stem cells, highly therapy-resistant cells that preferentially drive tumorigenesis and progression. This integrated genomic approach revealed an unexpected utilization of immuno-regulatory signals by pancreatic cancer epithelial cells. Read More

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https://linkinghub.elsevier.com/retrieve/pii/S00928674193027
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http://dx.doi.org/10.1016/j.cell.2019.03.010DOI Listing
April 2019
15 Reads

The Chaperonin TRiC/CCT Associates with Prefoldin through a Conserved Electrostatic Interface Essential for Cellular Proteostasis.

Cell 2019 Apr 4;177(3):751-765.e15. Epub 2019 Apr 4.

Department of Biology and Genetics, Stanford University, Stanford, CA 94305, USA. Electronic address:

Maintaining proteostasis in eukaryotic protein folding involves cooperation of distinct chaperone systems. To understand how the essential ring-shaped chaperonin TRiC/CCT cooperates with the chaperone prefoldin/GIMc (PFD), we integrate cryoelectron microscopy (cryo-EM), crosslinking-mass-spectrometry and biochemical and cellular approaches to elucidate the structural and functional interplay between TRiC/CCT and PFD. We find these hetero-oligomeric chaperones associate in a defined architecture, through a conserved interface of electrostatic contacts that serves as a pivot point for a TRiC-PFD conformational cycle. Read More

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http://dx.doi.org/10.1016/j.cell.2019.03.012DOI Listing
April 2019
1 Read

ATG8-Binding UIM Proteins Define a New Class of Autophagy Adaptors and Receptors.

Cell 2019 Apr 4;177(3):766-781.e24. Epub 2019 Apr 4.

Department of Biology, Washington University in St. Louis, St. Louis, MO 63130, USA. Electronic address:

During autophagy, vesicle dynamics and cargo recruitment are driven by numerous adaptors and receptors that become tethered to the phagophore through interactions with lipidated ATG8/LC3 decorating the expanding membrane. Most currently described ATG8-binding proteins exploit a well-defined ATG8-interacting motif (AIM, or LC3-interacting region [LIR]) that contacts a hydrophobic patch on ATG8 known as the LIR/AIM docking site (LDS). Here we describe a new class of ATG8 interactors that exploit ubiquitin-interacting motif (UIM)-like sequences for high-affinity binding to an alternative ATG8 interaction site. Read More

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http://dx.doi.org/10.1016/j.cell.2019.02.009DOI Listing

Unleashing Type-2 Dendritic Cells to Drive Protective Antitumor CD4 T Cell Immunity.

Cell 2019 Apr 4;177(3):556-571.e16. Epub 2019 Apr 4.

Department of Pathology, University of California, San Francisco, San Francisco, CA 94143, USA; UCSF Immunoprofiler Initiative, University of California, San Francisco, San Francisco, CA 94143, USA. Electronic address:

Differentiation of proinflammatory CD4 conventional T cells (T) is critical for productive antitumor responses yet their elicitation remains poorly understood. We comprehensively characterized myeloid cells in tumor draining lymph nodes (tdLN) of mice and identified two subsets of conventional type-2 dendritic cells (cDC2) that traffic from tumor to tdLN and present tumor-derived antigens to CD4 T, but then fail to support antitumor CD4 T differentiation. Regulatory T cell (T) depletion enhanced their capacity to elicit strong CD4 T responses and ensuing antitumor protection. Read More

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http://dx.doi.org/10.1016/j.cell.2019.02.005DOI Listing
April 2019
1 Read

Integrins and Their Role in Immune Cell Adhesion.

Authors:
Michael L Dustin

Cell 2019 Apr 2;177(3):499-501. Epub 2019 Apr 2.

Kennedy Institute of Rheumatology, NDORMS, The University of Oxford, Oxfordshire OX3 7FY, UK. Electronic address:

One of the 2019 Canada Gairdner International Awards recognizes Timothy Springer's discovery of the first immune system adhesion molecules involved in lymphocyte homing and the translation of those discoveries into therapeutics for autoimmune disease and cancer. Read More

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https://linkinghub.elsevier.com/retrieve/pii/S00928674193033
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http://dx.doi.org/10.1016/j.cell.2019.03.038DOI Listing
April 2019
3 Reads

Reflections on My Life with Taxol.

Cell 2019 Apr 2;177(3):502-505. Epub 2019 Apr 2.

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http://dx.doi.org/10.1016/j.cell.2019.03.031DOI Listing

Keep Your Eyes on the Prize.

Authors:
Ronald D Vale

Cell 2019 Apr 2;177(3):506-509. Epub 2019 Apr 2.

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http://dx.doi.org/10.1016/j.cell.2019.03.039DOI Listing

Evolving as a Scientist and a Mentor.

Authors:

Cell 2019 Apr 2;177(3):510-513. Epub 2019 Apr 2.

Connie Eaves sets high standards for herself, her science, and her colleagues, which has fueled a stellar career that counts as successes insights into basic stem cell biology, important discoveries in leukemia and breast cancer, and a cohort of trainees that she considers family. Cell editor Lara Szewczak caught up with Connie, the recipient of the 2019 Canada Gairdner Wightman Award, to discuss her dual passions for stem cell biology and mentoring talented young scientists. Annotated excerpts from this conversation are presented below. Read More

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http://dx.doi.org/10.1016/j.cell.2019.03.033DOI Listing
April 2019
1 Read

Once and Only Once.

Authors:
Susan Gasser

Cell 2019 Apr 2;177(3):495-498. Epub 2019 Apr 2.

Friedrich Miescher Institute for Biomedical Research, Maulbeerstrasse 66, 4058 Basel, Switzerland; University of Basel, Faculty of Natural Sciences, Klingelbergstrasse 70, 4056 Basel, Switzerland. Electronic address:

The 2019 Gairdner Prize will be given to John F.X. Diffley and Bruce Stillman for their groundbreaking work on the mechanisms and control of the initiation of eukaryotic DNA replication. Read More

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http://dx.doi.org/10.1016/j.cell.2019.03.034DOI Listing

exRNA Atlas Analysis Reveals Distinct Extracellular RNA Cargo Types and Their Carriers Present across Human Biofluids.

Cell 2019 Apr;177(2):463-477.e15

Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA. Electronic address:

To develop a map of cell-cell communication mediated by extracellular RNA (exRNA), the NIH Extracellular RNA Communication Consortium created the exRNA Atlas resource (https://exrna-atlas.org). The Atlas version 4P1 hosts 5,309 exRNA-seq and exRNA qPCR profiles from 19 studies and a suite of analysis and visualization tools. Read More

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https://linkinghub.elsevier.com/retrieve/pii/S00928674193016
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http://dx.doi.org/10.1016/j.cell.2019.02.018DOI Listing
April 2019
5 Reads

Small RNA Sequencing across Diverse Biofluids Identifies Optimal Methods for exRNA Isolation.

Cell 2019 Apr;177(2):446-462.e16

Department of Obstetrics, Gynecology, and Reproductive Sciences and Sanford Consortium for Regenerative Medicine, University of California, San Diego, La Jolla, CA, USA. Electronic address:

Poor reproducibility within and across studies arising from lack of knowledge regarding the performance of extracellular RNA (exRNA) isolation methods has hindered progress in the exRNA field. A systematic comparison of 10 exRNA isolation methods across 5 biofluids revealed marked differences in the complexity and reproducibility of the resulting small RNA-seq profiles. The relative efficiency with which each method accessed different exRNA carrier subclasses was determined by estimating the proportions of extracellular vesicle (EV)-, ribonucleoprotein (RNP)-, and high-density lipoprotein (HDL)-specific miRNA signatures in each profile. Read More

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http://dx.doi.org/10.1016/j.cell.2019.03.024DOI Listing

Reassessment of Exosome Composition.

Cell 2019 Apr;177(2):428-445.e18

Department of Medicine, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Department of Cell and Developmental Biology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA; Veterans Affairs Medical Center, Nashville, TN 37232, USA. Electronic address:

The heterogeneity of small extracellular vesicles and presence of non-vesicular extracellular matter have led to debate about contents and functional properties of exosomes. Here, we employ high-resolution density gradient fractionation and direct immunoaffinity capture to precisely characterize the RNA, DNA, and protein constituents of exosomes and other non-vesicle material. Extracellular RNA, RNA-binding proteins, and other cellular proteins are differentially expressed in exosomes and non-vesicle compartments. Read More

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http://dx.doi.org/10.1016/j.cell.2019.02.029DOI Listing
April 2019
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Suppression of Exosomal PD-L1 Induces Systemic Anti-tumor Immunity and Memory.

Cell 2019 Apr;177(2):414-427.e13

Department of Urology, University of California, San Francisco, San Francisco, CA 94143, USA; Eli and Edith Broad Institute for Regeneration Medicine, University of California, San Francisco, San Francisco, CA 94143, USA; Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA 94143, USA. Electronic address:

PD-L1 on the surface of tumor cells binds its receptor PD-1 on effector T cells, thereby suppressing their activity. Antibody blockade of PD-L1 can activate an anti-tumor immune response leading to durable remissions in a subset of cancer patients. Here, we describe an alternative mechanism of PD-L1 activity involving its secretion in tumor-derived exosomes. Read More

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http://dx.doi.org/10.1016/j.cell.2019.02.016DOI Listing

Structure of Microbial Nanowires Reveals Stacked Hemes that Transport Electrons over Micrometers.

Cell 2019 Apr;177(2):361-369.e10

Microbial Sciences Institute, Yale University, New Haven, CT 06516, USA; Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, CT 06511, USA. Electronic address:

Long-range (>10 μm) transport of electrons along networks of Geobacter sulfurreducens protein filaments, known as microbial nanowires, has been invoked to explain a wide range of globally important redox phenomena. These nanowires were previously thought to be type IV pili composed of PilA protein. Here, we report a 3. Read More

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https://linkinghub.elsevier.com/retrieve/pii/S00928674193029
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http://dx.doi.org/10.1016/j.cell.2019.03.029DOI Listing
April 2019
17 Reads

The Extracellular RNA Communication Consortium: Establishing Foundational Knowledge and Technologies for Extracellular RNA Research.

Cell 2019 Apr;177(2):231-242

Department of Obstetrics, Gynecology, and Reproductive Sciences and Sanford Consortium for Regenerative Medicine, University of California, San Diego, La Jolla, CA 92093, USA. Electronic address:

The Extracellular RNA Communication Consortium (ERCC) was launched to accelerate progress in the new field of extracellular RNA (exRNA) biology and to establish whether exRNAs and their carriers, including extracellular vesicles (EVs), can mediate intercellular communication and be utilized for clinical applications. Phase 1 of the ERCC focused on exRNA/EV biogenesis and function, discovery of exRNA biomarkers, development of exRNA/EV-based therapeutics, and construction of a robust set of reference exRNA profiles for a variety of biofluids. Here, we present progress by ERCC investigators in these areas, and we discuss collaborative projects directed at development of robust methods for EV/exRNA isolation and analysis and tools for sharing and computational analysis of exRNA profiling data. Read More

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http://dx.doi.org/10.1016/j.cell.2019.03.023DOI Listing
April 2019
2 Reads

Mapping Extracellular RNA Sheds Lights on Distinct Carriers.

Authors:
Cecilia Lässer

Cell 2019 Apr;177(2):228-230

Krefting Research Centre, Institute of Medicine at the Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden. Electronic address:

Circulating extracellular RNA can participate in cell-to-cell communication and can be used as a marker of disease. Currently, biological and technical variability prevents the field from reaching its full potential. In this issue of Cell and the April 24 issue of Cell Systems, three studies by the Extracellular RNA Communication Consortium (ERCC) (Murillo et al. Read More

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http://dx.doi.org/10.1016/j.cell.2019.03.027DOI Listing
April 2019
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Explicating Exosomes: Reclassifying the Rising Stars of Intercellular Communication.

Cell 2019 Apr;177(2):225-227

Cambridge Innovation Technologies Consulting (CITC) Limited, UK.

There is growing interest surrounding the diagnostic and therapeutic potential of exosomes, but a definitive description of these extracellular vesicles remains elusive. In this issue, Jeppesen et al. characterize exosomes following a strict isolation protocol and in so doing challenge several of the accepted properties of these agents of intercellular communication. Read More

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http://dx.doi.org/10.1016/j.cell.2019.03.020DOI Listing
April 2019
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Counting Calories: The Cost of Inflammation.

Cell 2019 Apr;177(2):223-224

Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06520, USA; Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, CT 06520, USA. Electronic address:

A relationship between thermoregulation, metabolism, and the host response to infections has long been appreciated. In this study, Ganeshan and colleagues discover that the immune system regulates body temperature as a strategy to regulate metabolic rate, which in turn promotes tolerance to inflammatory damage. Read More

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http://dx.doi.org/10.1016/j.cell.2019.03.022DOI Listing

Does Autophagy Promote Longevity? It Depends.

Cell 2019 Apr;177(2):221-222

Program in Developmental Biology, Baylor College of Medicine, Houston, TX 77030, USA; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Huffington Center on Aging, Baylor College of Medicine, Houston, TX 77030, USA; Howard Hughes Medical Institute, Baylor College of Medicine, Houston, TX 77030, USA. Electronic address:

Zhou et al. challenge the well-known beneficial effect of autophagy in promoting longevity. Evidence presented demonstrate that autophagy induction coupled with increased mitochondrial permeability is detrimental to organismal health in both the nematode Caenorhabditis elegans and mammals. Read More

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http://dx.doi.org/10.1016/j.cell.2019.03.021DOI Listing

Steroid Hormone Function Controls Non-competitive Plasmodium Development in Anopheles.

Cell 2019 Apr 28;177(2):315-325.e14. Epub 2019 Mar 28.

Department of Immunology and Infectious Diseases, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA. Electronic address:

Transmission of malaria parasites occurs when a female Anopheles mosquito feeds on an infected host to acquire nutrients for egg development. How parasites are affected by oogenetic processes, principally orchestrated by the steroid hormone 20-hydroxyecdysone (20E), remains largely unknown. Here we show that Plasmodium falciparum development is intimately but not competitively linked to processes shaping Anopheles gambiae reproduction. Read More

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http://dx.doi.org/10.1016/j.cell.2019.02.036DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6450776PMC
April 2019
1 Read

Shared Cortex-Cerebellum Dynamics in the Execution and Learning of a Motor Task.

Cell 2019 Apr 28;177(3):669-682.e24. Epub 2019 Mar 28.

Department of Biology, Stanford University, Stanford, CA 94305, USA; Howard Hughes Medical Institute, Stanford University, Stanford, CA 94305, USA. Electronic address:

Throughout mammalian neocortex, layer 5 pyramidal (L5) cells project via the pons to a vast number of cerebellar granule cells (GrCs), forming a fundamental pathway. Yet, it is unknown how neuronal dynamics are transformed through the L5→GrC pathway. Here, by directly comparing premotor L5 and GrC activity during a forelimb movement task using dual-site two-photon Ca imaging, we found that in expert mice, L5 and GrC dynamics were highly similar. Read More

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http://dx.doi.org/10.1016/j.cell.2019.02.019DOI Listing

The 26S Proteasome Utilizes a Kinetic Gateway to Prioritize Substrate Degradation.

Cell 2019 Apr 28;177(2):286-298.e15. Epub 2019 Mar 28.

Department of Molecular and Cell Biology, University of California at Berkeley, Berkeley, CA 94720, USA; California Institute for Quantitative Biosciences, University of California at Berkeley, Berkeley, CA 94720, USA; Howard Hughes Medical Institute, University of California at Berkeley, Berkeley, CA 94720, USA. Electronic address:

The 26S proteasome is the principal macromolecular machine responsible for protein degradation in eukaryotes. However, little is known about the detailed kinetics and coordination of the underlying substrate-processing steps of the proteasome, and their correlation with observed conformational states. Here, we used reconstituted 26S proteasomes with unnatural amino-acid-attached fluorophores in a series of FRET- and anisotropy-based assays to probe substrate-proteasome interactions, the individual steps of the processing pathway, and the conformational state of the proteasome itself. Read More

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http://dx.doi.org/10.1016/j.cell.2019.02.031DOI Listing
April 2019
1 Read