Journal Cover Cell
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   ISSN (Print) 0092-8674 - ISSN (Online) 1097-4172
   Published by Elsevier Homepage  [3031 journals]
  • Bringing Culture to Bacteria
    • Abstract: Publication date: 20 April 2017
      Source:Cell, Volume 169, Issue 3
      Author(s): Mirna Kvajo


      PubDate: 2017-04-24T05:00:52Z
       
  • Reducing Recurrence of C. difficile Infection
    • Abstract: Publication date: 20 April 2017
      Source:Cell, Volume 169, Issue 3
      Author(s): Michael G. Dieterle, Vincent B. Young
      Clostridium difficile infection (CDI) is facilitated by alteration of the microbiome following antibiotic administration. Antimicrobial therapy directed against the pathogen can treat CDI. Unfortunately, ∼20% of successfully treated patients will suffer recurrence. Bezlotoxumab, a human monoclonal antibody, binds to C. difficile toxin B (TcdB), reducing recurrence presumably by limiting epithelial damage and facilitating microbiome recovery.
      Teaser Clostridium difficile infection (CDI) is facilitated by alteration of the microbiome following antibiotic administration. Antimicrobial therapy directed against the pathogen can treat CDI. Unfortunately, ∼20% of successfully treated patients will suffer recurrence. Bezlotoxumab, a human monoclonal antibody, binds to C. difficile toxin B (TcdB), reducing recurrence presumably by limiting epithelial damage and facilitating microbiome recovery.

      PubDate: 2017-04-24T05:00:52Z
       
  • Resident Macrophages: Near and Dear to Your Heart
    • Abstract: Publication date: 20 April 2017
      Source:Cell, Volume 169, Issue 3
      Author(s): Nikhil V. Munshi
      In this issue of Cell, Hulsmans et al. identify a subset of macrophages residing within the cardiac conduction system, which orchestrates cardiac rhythm. Macrophages directly couple with cardiomyocytes, and their perturbation alters cardiac conduction, suggesting that pharmacological manipulation of resident macrophages might represent a new strategy to combat cardiac arrhythmias.
      Teaser In this issue of Cell, Hulsmans et al. identify a subset of macrophages residing within the cardiac conduction system, which orchestrates cardiac rhythm. Macrophages directly couple with cardiomyocytes, and their perturbation alters cardiac conduction, suggesting that pharmacological manipulation of resident macrophages might represent a new strategy to combat cardiac arrhythmias.

      PubDate: 2017-04-24T05:00:52Z
       
  • Building a Translational Microbiome Toolbox
    • Abstract: Publication date: 20 April 2017
      Source:Cell, Volume 169, Issue 3
      Author(s): Payal Joglekar, Julia A. Segre
      Designing successful microbiota-based therapies requires in-depth understanding of the ecological foundations of this community. In this issue, two studies by Whitaker et al. and Lim et al. provide refined genetic tools for dissecting the spatial organization and temporal dynamics of bacterial communities at the single-cell and -gene levels.
      Teaser Designing successful microbiota-based therapies requires in-depth understanding of the ecological foundations of this community. In this issue, two studies by Whitaker et al. and Lim et al. provide refined genetic tools for dissecting the spatial organization and temporal dynamics of bacterial communities at the single-cell and -gene levels.

      PubDate: 2017-04-24T05:00:52Z
       
  • AKT/PKB Signaling: Navigating the Network
    • Abstract: Publication date: 20 April 2017
      Source:Cell, Volume 169, Issue 3
      Author(s): Brendan D. Manning, Alex Toker
      The Ser and Thr kinase AKT, also known as protein kinase B (PKB), was discovered 25 years ago and has been the focus of tens of thousands of studies in diverse fields of biology and medicine. There have been many advances in our knowledge of the upstream regulatory inputs into AKT, key multifunctional downstream signaling nodes (GSK3, FoxO, mTORC1), which greatly expand the functional repertoire of AKT, and the complex circuitry of this dynamically branching and looping signaling network that is ubiquitous to nearly every cell in our body. Mouse and human genetic studies have also revealed physiological roles for the AKT network in nearly every organ system. Our comprehension of AKT regulation and functions is particularly important given the consequences of AKT dysfunction in diverse pathological settings, including developmental and overgrowth syndromes, cancer, cardiovascular disease, insulin resistance and type 2 diabetes, inflammatory and autoimmune disorders, and neurological disorders. There has also been much progress in developing AKT-selective small molecule inhibitors. Improved understanding of the molecular wiring of the AKT signaling network continues to make an impact that cuts across most disciplines of the biomedical sciences.
      Teaser 25 years since its initial discovery, the serine/threonine kinase AKT has been found to be a critical regulator of multiple cellular processes and its dysfunction associated with a range of human diseases.

      PubDate: 2017-04-24T05:00:52Z
       
  • Structural and Functional Analysis of a β2-Adrenergic Receptor
           Complex with GRK5
    • Abstract: Publication date: 20 April 2017
      Source:Cell, Volume 169, Issue 3
      Author(s): Konstantin E. Komolov, Yang Du, Nguyen Minh Duc, Robin M. Betz, João P.G.L.M. Rodrigues, Ryan D. Leib, Dhabaleswar Patra, Georgios Skiniotis, Christopher M. Adams, Ron O. Dror, Ka Young Chung, Brian K. Kobilka, Jeffrey L. Benovic
      The phosphorylation of agonist-occupied G-protein-coupled receptors (GPCRs) by GPCR kinases (GRKs) functions to turn off G-protein signaling and turn on arrestin-mediated signaling. While a structural understanding of GPCR/G-protein and GPCR/arrestin complexes has emerged in recent years, the molecular architecture of a GPCR/GRK complex remains poorly defined. We used a comprehensive integrated approach of cross-linking, hydrogen-deuterium exchange mass spectrometry (MS), electron microscopy, mutagenesis, molecular dynamics simulations, and computational docking to analyze GRK5 interaction with the β2-adrenergic receptor (β2AR). These studies revealed a dynamic mechanism of complex formation that involves large conformational changes in the GRK5 RH/catalytic domain interface upon receptor binding. These changes facilitate contacts between intracellular loops 2 and 3 and the C terminus of the β2AR with the GRK5 RH bundle subdomain, membrane-binding surface, and kinase catalytic cleft, respectively. These studies significantly contribute to our understanding of the mechanism by which GRKs regulate the function of activated GPCRs. PaperClip
      Graphical abstract image Teaser Biophysical analysis of a G-protein-coupled receptor (GPCR) complex with a GPCR kinase reveals significant conformational changes in the kinase that are essential for effective receptor phosphorylation.

      PubDate: 2017-04-24T05:00:52Z
       
  • Cryo-EM Structure of the Open Human Ether-à-go-go-Related K+ Channel
           hERG
    • Abstract: Publication date: 20 April 2017
      Source:Cell, Volume 169, Issue 3
      Author(s): Weiwei Wang, Roderick MacKinnon
      The human ether-à-go-go-related potassium channel (hERG, Kv11.1) is a voltage-dependent channel known for its role in repolarizing the cardiac action potential. hERG alteration by mutation or pharmacological inhibition produces Long QT syndrome and the lethal cardiac arrhythmia torsade de pointes. We have determined the molecular structure of hERG to 3.8 Å using cryo-electron microscopy. In this structure, the voltage sensors adopt a depolarized conformation, and the pore is open. The central cavity has an atypically small central volume surrounded by four deep hydrophobic pockets, which may explain hERG’s unusual sensitivity to many drugs. A subtle structural feature of the hERG selectivity filter might correlate with its fast inactivation rate, which is key to hERG’s role in cardiac action potential repolarization.
      Graphical abstract image Teaser Structural analysis of the hERG channel helps to understand known human channelopathy mutations and why the channel is extremely sensitive to a wide range of drugs.

      PubDate: 2017-04-24T05:00:52Z
       
  • Bacterial Metabolism Affects the C. elegans Response to Cancer
           Chemotherapeutics
    • Abstract: Publication date: 20 April 2017
      Source:Cell, Volume 169, Issue 3
      Author(s): Aurian P. García-González, Ashlyn D. Ritter, Shaleen Shrestha, Erik C. Andersen, L. Safak Yilmaz, Albertha J.M. Walhout
      The human microbiota greatly affects physiology and disease; however, the contribution of bacteria to the response to chemotherapeutic drugs remains poorly understood. Caenorhabditis elegans and its bacterial diet provide a powerful system to study host-bacteria interactions. Here, we use this system to study how bacteria affect the C. elegans response to chemotherapeutics. We find that different bacterial species can increase the response to one drug yet decrease the effect of another. We perform genetic screens in two bacterial species using three chemotherapeutic drugs: 5-fluorouracil (5-FU), 5-fluoro-2′-deoxyuridine (FUDR), and camptothecin (CPT). We find numerous bacterial nucleotide metabolism genes that affect drug efficacy in C. elegans. Surprisingly, we find that 5-FU and FUDR act through bacterial ribonucleotide metabolism to elicit their cytotoxic effects in C. elegans rather than by thymineless death or DNA damage. Our study provides a blueprint for characterizing the role of bacteria in the host response to chemotherapeutics.
      Graphical abstract image Teaser Genetic screens reveal that bacteria modulate host chemotherapeutic drug response by active metabolic mechanisms.

      PubDate: 2017-04-24T05:00:52Z
       
  • Host-Microbe Co-metabolism Dictates Cancer Drug Efficacy in
           C. elegans
    • Abstract: Publication date: 20 April 2017
      Source:Cell, Volume 169, Issue 3
      Author(s): Timothy A. Scott, Leonor M. Quintaneiro, Povilas Norvaisas, Prudence P. Lui, Matthew P. Wilson, Kit-Yi Leung, Lucia Herrera-Dominguez, Sonia Sudiwala, Alberto Pessia, Peter T. Clayton, Kevin Bryson, Vidya Velagapudi, Philippa B. Mills, Athanasios Typas, Nicholas D.E. Greene, Filipe Cabreiro
      Fluoropyrimidines are the first-line treatment for colorectal cancer, but their efficacy is highly variable between patients. We queried whether gut microbes, a known source of inter-individual variability, impacted drug efficacy. Combining two tractable genetic models, the bacterium E. coli and the nematode C. elegans, we performed three-way high-throughput screens that unraveled the complexity underlying host-microbe-drug interactions. We report that microbes can bolster or suppress the effects of fluoropyrimidines through metabolic drug interconversion involving bacterial vitamin B6, B9, and ribonucleotide metabolism. Also, disturbances in bacterial deoxynucleotide pools amplify 5-FU-induced autophagy and cell death in host cells, an effect regulated by the nucleoside diphosphate kinase ndk-1. Our data suggest a two-way bacterial mediation of fluoropyrimidine effects on host metabolism, which contributes to drug efficacy. These findings highlight the potential therapeutic power of manipulating intestinal microbiota to ensure host metabolic health and treat disease.
      Graphical abstract image Teaser A three-way high-throughput screen involving host-microbe-drug interactions reveals that the beneficial impact of some drugs can be due to effects of drug-dependent alterations by gut microbe composition rather than direct action of the therapeutic itself.

      PubDate: 2017-04-24T05:00:52Z
       
  • Fatty Acids Regulate Germline Sex Determination through ACS-4-Dependent
           Myristoylation
    • Abstract: Publication date: 20 April 2017
      Source:Cell, Volume 169, Issue 3
      Author(s): Hongyun Tang, Min Han
      Fat metabolism has been linked to fertility and reproductive adaptation in animals and humans, and environmental sex determination potentially plays a role in the process. To investigate the impact of fatty acids (FA) on sex determination and reproductive development, we examined and observed an impact of FA synthesis and mobilization by lipolysis in somatic tissues on oocyte fate in Caenorhabditis elegans. The subsequent genetic analysis identified ACS-4, an acyl-CoA synthetase and its FA-CoA product, as key germline factors that mediate the role of FA in promoting oocyte fate through protein myristoylation. Further tests indicated that ACS-4-dependent protein myristoylation perceives and translates the FA level into regulatory cues that modulate the activities of MPK-1/MAPK and key factors in the germline sex-determination pathway. These findings, including a similar role of ACS-4 in a male/female species, uncover a likely conserved mechanism by which FA, an environmental factor, regulates sex determination and reproductive development.
      Graphical abstract image Teaser For worms, fatty acids regulate germ cell fate specification during development by modulating germline sex determination.

      PubDate: 2017-04-24T05:00:52Z
       
  • The Ubiquitin Ligase CHIP Integrates Proteostasis and Aging by Regulation
           of Insulin Receptor Turnover
    • Abstract: Publication date: 20 April 2017
      Source:Cell, Volume 169, Issue 3
      Author(s): Riga Tawo, Wojciech Pokrzywa, Éva Kevei, Melek E. Akyuz, Vishnu Balaji, Svenja Adrian, Jörg Höhfeld, Thorsten Hoppe
      Aging is attended by a progressive decline in protein homeostasis (proteostasis), aggravating the risk for protein aggregation diseases. To understand the coordination between proteome imbalance and longevity, we addressed the mechanistic role of the quality-control ubiquitin ligase CHIP, which is a key regulator of proteostasis. We observed that CHIP deficiency leads to increased levels of the insulin receptor (INSR) and reduced lifespan of worms and flies. The membrane-bound INSR regulates the insulin and IGF1 signaling (IIS) pathway and thereby defines metabolism and aging. INSR is a direct target of CHIP, which triggers receptor monoubiquitylation and endocytic-lysosomal turnover to promote longevity. However, upon proteotoxic stress conditions and during aging, CHIP is recruited toward disposal of misfolded proteins, reducing its capacity to degrade the INSR. Our study indicates a competitive relationship between proteostasis and longevity regulation through CHIP-assisted proteolysis, providing a mechanistic concept for understanding the impact of proteome imbalance on aging.
      Graphical abstract image Teaser A ubiquitin ligase promotes either longevity or proteostasis, depending on the cellular status.

      PubDate: 2017-04-24T05:00:52Z
       
  • Spontaneous Chitin Accumulation in Airways and Age-Related Fibrotic Lung
           Disease
    • Abstract: Publication date: 20 April 2017
      Source:Cell, Volume 169, Issue 3
      Author(s): Steven J. Van Dyken, Hong-Erh Liang, Ram P. Naikawadi, Prescott G. Woodruff, Paul J. Wolters, David J. Erle, Richard M. Locksley
      The environmentally widespread polysaccharide chitin is degraded and recycled by ubiquitous bacterial and fungal chitinases. Although vertebrates express active chitinases from evolutionarily conserved loci, their role in mammalian physiology is unclear. We show that distinct lung epithelial cells secrete acidic mammalian chitinase (AMCase), which is required for airway chitinase activity. AMCase-deficient mice exhibit premature morbidity and mortality, concomitant with accumulation of environmentally derived chitin polymers in the airways and expression of pro-fibrotic cytokines. Over time, these mice develop spontaneous pulmonary fibrosis, which is ameliorated by restoration of lung chitinase activity by genetic or therapeutic approaches. AMCase-deficient epithelial cells express fibrosis-associated gene sets linked with cell stress pathways. Mice with lung fibrosis due to telomere dysfunction and humans with interstitial lung disease also accumulate excess chitin polymers in their airways. These data suggest that altered chitin clearance could exacerbate fibrogenic pathways in the setting of lung diseases characterized by epithelial cell dysfunction.
      Graphical abstract image Teaser An ancient enzyme protects the lungs from damaging effects of a widespread environmental polysaccharide.

      PubDate: 2017-04-24T05:00:52Z
       
  • Macrophages Facilitate Electrical Conduction in the Heart
    • Abstract: Publication date: 20 April 2017
      Source:Cell, Volume 169, Issue 3
      Author(s): Maarten Hulsmans, Sebastian Clauss, Ling Xiao, Aaron D. Aguirre, Kevin R. King, Alan Hanley, William J. Hucker, Eike M. Wülfers, Gunnar Seemann, Gabriel Courties, Yoshiko Iwamoto, Yuan Sun, Andrej J. Savol, Hendrik B. Sager, Kory J. Lavine, Gregory A. Fishbein, Diane E. Capen, Nicolas Da Silva, Lucile Miquerol, Hiroko Wakimoto, Christine E. Seidman, Jonathan G. Seidman, Ruslan I. Sadreyev, Kamila Naxerova, Richard N. Mitchell, Dennis Brown, Peter Libby, Ralph Weissleder, Filip K. Swirski, Peter Kohl, Claudio Vinegoni, David J. Milan, Patrick T. Ellinor, Matthias Nahrendorf
      Organ-specific functions of tissue-resident macrophages in the steady-state heart are unknown. Here, we show that cardiac macrophages facilitate electrical conduction through the distal atrioventricular node, where conducting cells densely intersperse with elongated macrophages expressing connexin 43. When coupled to spontaneously beating cardiomyocytes via connexin-43-containing gap junctions, cardiac macrophages have a negative resting membrane potential and depolarize in synchrony with cardiomyocytes. Conversely, macrophages render the resting membrane potential of cardiomyocytes more positive and, according to computational modeling, accelerate their repolarization. Photostimulation of channelrhodopsin-2-expressing macrophages improves atrioventricular conduction, whereas conditional deletion of connexin 43 in macrophages and congenital lack of macrophages delay atrioventricular conduction. In the Cd11b DTR mouse, macrophage ablation induces progressive atrioventricular block. These observations implicate macrophages in normal and aberrant cardiac conduction.
      Graphical abstract image Teaser Heart-resident macrophages directly modulate the electrical properties of cardiomyocytes.

      PubDate: 2017-04-24T05:00:52Z
       
  • Nuclear Proximity of Mtr4 to RNA Exosome Restricts DNA Mutational
           Asymmetry
    • Abstract: Publication date: 20 April 2017
      Source:Cell, Volume 169, Issue 3
      Author(s): Junghyun Lim, Pankaj Kumar Giri, David Kazadi, Brice Laffleur, Wanwei Zhang, Veronika Grinstein, Evangelos Pefanis, Lewis M. Brown, Erik Ladewig, Ophélie Martin, Yuling Chen, Raul Rabadan, François Boyer, Gerson Rothschild, Michel Cogné, Eric Pinaud, Haiteng Deng, Uttiya Basu
      The distribution of sense and antisense strand DNA mutations on transcribed duplex DNA contributes to the development of immune and neural systems along with the progression of cancer. Because developmentally matured B cells undergo biologically programmed strand-specific DNA mutagenesis at focal DNA/RNA hybrid structures, they make a convenient system to investigate strand-specific mutagenesis mechanisms. We demonstrate that the sense and antisense strand DNA mutagenesis at the immunoglobulin heavy chain locus and some other regions of the B cell genome depends upon localized RNA processing protein complex formation in the nucleus. Both the physical proximity and coupled activities of RNA helicase Mtr4 (and senataxin) with the noncoding RNA processing function of RNA exosome determine the strand-specific distribution of DNA mutations. Our study suggests that strand-specific DNA mutagenesis-associated mechanisms will play major roles in other undiscovered aspects of organismic development.
      Graphical abstract image Teaser Limitation of local RNA-DNA structures restricts DNA mutational asymmetry.

      PubDate: 2017-04-24T05:00:52Z
       
  • Tunable Expression Tools Enable Single-Cell Strain Distinction in the Gut
           Microbiome
    • Abstract: Publication date: 20 April 2017
      Source:Cell, Volume 169, Issue 3
      Author(s): Weston R. Whitaker, Elizabeth Stanley Shepherd, Justin L. Sonnenburg
      Applying synthetic biology to engineer gut-resident microbes provides new avenues to investigate microbe-host interactions, perform diagnostics, and deliver therapeutics. Here, we describe a platform for engineering Bacteroides, the most abundant genus in the Western microbiota, which includes a process for high-throughput strain modification. We have identified a novel phage promoter and translational tuning strategy and achieved an unprecedented level of expression that enables imaging of fluorescent-protein-expressing Bacteroides stably colonizing the mouse gut. A detailed characterization of the phage promoter has provided a set of constitutive promoters that span over four logs of strength without detectable fitness burden within the gut over 14 days. These promoters function predictably over a 1,000,000-fold expression range in phylogenetically diverse Bacteroides species. With these promoters, unique fluorescent signatures were encoded to allow differentiation of six species within the gut. Fluorescent protein-based differentiation of isogenic strains revealed that priority of gut colonization determines colonic crypt occupancy.
      Graphical abstract image Teaser A synthetic biology platform to engineer Bacteroides species enables strain-level distinction of gut bacterial cells in vivo.

      PubDate: 2017-04-24T05:00:52Z
       
  • Engineered Regulatory Systems Modulate Gene Expression of Human Commensals
           in the Gut
    • Abstract: Publication date: 20 April 2017
      Source:Cell, Volume 169, Issue 3
      Author(s): Bentley Lim, Michael Zimmermann, Natasha A. Barry, Andrew L. Goodman
      The gut microbiota is implicated in numerous aspects of health and disease, but dissecting these connections is challenging because genetic tools for gut anaerobes are limited. Inducible promoters are particularly valuable tools because these platforms allow real-time analysis of the contribution of microbiome gene products to community assembly, host physiology, and disease. We developed a panel of tunable expression platforms for the prominent genus Bacteroides in which gene expression is controlled by a synthetic inducer. In the absence of inducer, promoter activity is fully repressed; addition of inducer rapidly increases gene expression by four to five orders of magnitude. Because the inducer is absent in mice and their diets, Bacteroides gene expression inside the gut can be modulated by providing the inducer in drinking water. We use this system to measure the dynamic relationship between commensal sialidase activity and liberation of mucosal sialic acid, a receptor and nutrient for pathogens. Video
      Graphical abstract image Teaser New tools enable modulating gene expression of anaerobe members of the microbiome inside the gut through introduction of a synthetic inducer in drinking water.

      PubDate: 2017-04-24T05:00:52Z
       
  • Hypothalamic Agrp Neurons Drive Stereotypic Behaviors beyond Feeding
    • Abstract: Publication date: 20 April 2017
      Source:Cell, Volume 169, Issue 3
      Author(s): Marcelo O. Dietrich, Marcelo R. Zimmer, Jeremy Bober, Tamas L. Horvath


      PubDate: 2017-04-24T05:00:52Z
       
  • CRISPR-Based Technologies for the Manipulation of Eukaryotic Genomes
    • Abstract: Publication date: 20 April 2017
      Source:Cell, Volume 169, Issue 3
      Author(s): Alexis C. Komor, Ahmed H. Badran, David R. Liu


      PubDate: 2017-04-24T05:00:52Z
       
  • Stem Cell Lineage Infidelity Drives Wound Repair and Cancer
    • Abstract: Publication date: Available online 20 April 2017
      Source:Cell
      Author(s): Yejing Ge, Nicholas C. Gomez, Rene C. Adam, Maria Nikolova, Hanseul Yang, Akanksha Verma, Catherine Pei-Ju Lu, Lisa Polak, Shaopeng Yuan, Olivier Elemento, Elaine Fuchs
      Tissue stem cells contribute to tissue regeneration and wound repair through cellular programs that can be hijacked by cancer cells. Here, we investigate such a phenomenon in skin, where during homeostasis, stem cells of the epidermis and hair follicle fuel their respective tissues. We find that breakdown of stem cell lineage confinement—granting privileges associated with both fates—is not only hallmark but also functional in cancer development. We show that lineage plasticity is critical in wound repair, where it operates transiently to redirect fates. Investigating mechanism, we discover that irrespective of cellular origin, lineage infidelity occurs in wounding when stress-responsive enhancers become activated and override homeostatic enhancers that govern lineage specificity. In cancer, stress-responsive transcription factor levels rise, causing lineage commanders to reach excess. When lineage and stress factors collaborate, they activate oncogenic enhancers that distinguish cancers from wounds.
      Graphical abstract image Teaser Stem cell lineage infidelity occurs transiently in wounds and persists in cancer, driving wound repair and malignancy.

      PubDate: 2017-04-24T05:00:52Z
       
  • Epithelial-Mesenchymal Micro-niches Govern Stem Cell Lineage Choices
    • Abstract: Publication date: Available online 13 April 2017
      Source:Cell
      Author(s): Hanseul Yang, Rene C. Adam, Yejing Ge, Zhong L. Hua, Elaine Fuchs
      Adult tissue stem cells (SCs) reside in niches, which, through intercellular contacts and signaling, influence SC behavior. Once activated, SCs typically give rise to short-lived transit-amplifying cells (TACs), which then progress to differentiate into their lineages. Here, using single-cell RNA-seq, we unearth unexpected heterogeneity among SCs and TACs of hair follicles. We trace the roots of this heterogeneity to micro-niches along epithelial-mesenchymal interfaces, where progenitors display molecular signatures reflective of spatially distinct local signals and intercellular interactions. Using lineage tracing, temporal single-cell analyses, and chromatin landscaping, we show that SC plasticity becomes restricted in a sequentially and spatially choreographed program, culminating in seven spatially arranged unilineage progenitors within TACs of mature follicles. By compartmentalizing SCs into micro-niches, tissues gain precise control over morphogenesis and regeneration: some progenitors specify lineages immediately, whereas others retain potency, preserving self-renewing features established early while progressively restricting lineages as they experience dynamic changes in microenvironment.
      Graphical abstract image Teaser Stem cells and their short lived proliferative progeny exhibit molecular heterogeneity set up by micro-niches in the regenerating hair follicle.

      PubDate: 2017-04-17T14:21:06Z
       
  • Choose Your Friends Wisely
    • Abstract: Publication date: 6 April 2017
      Source:Cell, Volume 169, Issue 2
      Author(s): Marta Koch


      PubDate: 2017-04-10T01:41:43Z
       
  • Going Public in Support of Science
    • Abstract: Publication date: 6 April 2017
      Source:Cell, Volume 169, Issue 2
      Author(s): Susan Matheson
      Scientists are stepping up like never before to support science in the public arena. In big and small ways, scientists are adopting creative ideas to promote science.
      Teaser Scientists are stepping up like never before to support science in the public arena. In big and small ways, scientists are adopting creative ways to promote science.

      PubDate: 2017-04-10T01:41:43Z
       
  • PARP Inhibitors for Cancer Therapy
    • Abstract: Publication date: 6 April 2017
      Source:Cell, Volume 169, Issue 2
      Author(s): Ken Y. Lin, W. Lee Kraus
      Rucaparib is an inhibitor of nuclear poly (ADP-ribose) polymerases (inhibition of PARP-1 > PARP-2 > PARP-3), following a similar drug, Olaparib. It disrupts DNA repair and replication pathways (and possibly transcription), leading to selective killing of cancer cells with BRCA1/2 mutations. Rucaparib is approved for recurrent ovarian cancers with germline or somatic mutations in BRCA1/2.
      Teaser Rucaparib is an inhibitor of nuclear poly (ADP-ribose) polymerases (inhibition of PARP-1 > PARP-2 > PARP-3), following a similar drug, Olaparib. It disrupts DNA repair and replication pathways (and possibly transcription), leading to selective killing of cancer cells with BRCA1/2 mutations. Rucaparib is approved for recurrent ovarian cancers with germline or somatic mutations in BRCA1/2.

      PubDate: 2017-04-10T01:41:43Z
       
  • Can We Just Say: Transcription Second'
    • Abstract: Publication date: 6 April 2017
      Source:Cell, Volume 169, Issue 2
      Author(s): Peter Hugo Lodewijk Krijger, Wouter de Laat
      The striking correlation between genome topology and transcriptional activity has for decades made researchers revisit the question, “Does form follow function, or does function follow form'” In a new study, Hug et al. address this question by comparing the timing of zygotic genome activation to the emergence of genome structures during Drosophila embryogenesis.
      Teaser The striking correlation between genome topology and transcriptional activity has for decades made researchers revisit the question, “Does form follow function, or does function follow form'” In a new study, Hug et al. address this question by comparing the timing of zygotic genome activation to the emergence of genome structures during Drosophila embryogenesis.

      PubDate: 2017-04-10T01:41:43Z
       
  • ESCRTing Necroptosis
    • Abstract: Publication date: 6 April 2017
      Source:Cell, Volume 169, Issue 2
      Author(s): Hongyan Guo, William J. Kaiser
      Necroptosis is a highly inflammatory form of programmed cell death that results from MLKL-mediated disruption of the cell membrane. In this issue of Cell, Gong et al. challenge the notion that MLKL activation is a point of no return by identifying mechanisms to counterbalance necroptosis, sustain plasma membrane integrity, and prolong cell viability.
      Teaser Necroptosis is a highly inflammatory form of programmed cell death that results from MLKL-mediated disruption of the cell membrane. In this issue of Cell, Gong et al. challenge the notion that MLKL activation is a point of no return by identifying mechanisms to counterbalance necroptosis, sustain plasma membrane integrity, and prolong cell viability.

      PubDate: 2017-04-10T01:41:43Z
       
  • Drosophilosophical: Re-thinking Adaptive Immunity in the Fly
    • Abstract: Publication date: 6 April 2017
      Source:Cell, Volume 169, Issue 2
      Author(s): Cara West, Neal Silverman
      For decades, flies have been a model for innate immunity. In this issue of Cell, Tassetto et al. describe a mechanism for antiviral RNAi spreading that parallels mammalian adaptive immunity through reverse-transcribed vDNA circles and the systemic dissemination of small-RNA-containing exosomes.
      Teaser For decades, flies have been a model for innate immunity. In this issue of Cell, Tassetto et al. describe a mechanism for antiviral RNAi spreading that parallels mammalian adaptive immunity through reverse-transcribed vDNA circles and the systemic dissemination of small-RNA-containing exosomes.

      PubDate: 2017-04-10T01:41:43Z
       
  • Trade-off between Transcriptome Plasticity and Genome Evolution in
           Cephalopods
    • Abstract: Publication date: 6 April 2017
      Source:Cell, Volume 169, Issue 2
      Author(s): Noa Liscovitch-Brauer, Shahar Alon, Hagit T. Porath, Boaz Elstein, Ron Unger, Tamar Ziv, Arie Admon, Erez Y. Levanon, Joshua J.C. Rosenthal, Eli Eisenberg
      RNA editing, a post-transcriptional process, allows the diversification of proteomes beyond the genomic blueprint; however it is infrequently used among animals for this purpose. Recent reports suggesting increased levels of RNA editing in squids thus raise the question of the nature and effects of these events. We here show that RNA editing is particularly common in behaviorally sophisticated coleoid cephalopods, with tens of thousands of evolutionarily conserved sites. Editing is enriched in the nervous system, affecting molecules pertinent for excitability and neuronal morphology. The genomic sequence flanking editing sites is highly conserved, suggesting that the process confers a selective advantage. Due to the large number of sites, the surrounding conservation greatly reduces the number of mutations and genomic polymorphisms in protein-coding regions. This trade-off between genome evolution and transcriptome plasticity highlights the importance of RNA recoding as a strategy for diversifying proteins, particularly those associated with neural function. PaperClip
      Graphical abstract image Teaser Behaviorally complex cephalopods use extensive RNA editing to diversify their neural proteome at the cost of limiting genomic sequence flexibility and evolution.

      PubDate: 2017-04-10T01:41:43Z
       
  • Mutation of the Human Circadian Clock Gene CRY1 in Familial Delayed Sleep
           Phase Disorder
    • Abstract: Publication date: 6 April 2017
      Source:Cell, Volume 169, Issue 2
      Author(s): Alina Patke, Patricia J. Murphy, Onur Emre Onat, Ana C. Krieger, Tayfun Özçelik, Scott S. Campbell, Michael W. Young
      Patterns of daily human activity are controlled by an intrinsic circadian clock that promotes ∼24 hr rhythms in many behavioral and physiological processes. This system is altered in delayed sleep phase disorder (DSPD), a common form of insomnia in which sleep episodes are shifted to later times misaligned with the societal norm. Here, we report a hereditary form of DSPD associated with a dominant coding variation in the core circadian clock gene CRY1, which creates a transcriptional inhibitor with enhanced affinity for circadian activator proteins Clock and Bmal1. This gain-of-function CRY1 variant causes reduced expression of key transcriptional targets and lengthens the period of circadian molecular rhythms, providing a mechanistic link to DSPD symptoms. The allele has a frequency of up to 0.6%, and reverse phenotyping of unrelated families corroborates late and/or fragmented sleep patterns in carriers, suggesting that it affects sleep behavior in a sizeable portion of the human population.
      Graphical abstract image Teaser A variation in the human circadian clock gene CRY1 is associated with a familial form of delayed sleep phase disorder, providing genetic underpinnings for “night owls.”

      PubDate: 2017-04-10T01:41:43Z
       
  • Chromatin Architecture Emerges during Zygotic Genome Activation
           Independent of Transcription
    • Abstract: Publication date: 6 April 2017
      Source:Cell, Volume 169, Issue 2
      Author(s): Clemens B. Hug, Alexis G. Grimaldi, Kai Kruse, Juan M. Vaquerizas
      Chromatin architecture is fundamental in regulating gene expression. To investigate when spatial genome organization is first established during development, we examined chromatin conformation during Drosophila embryogenesis and observed the emergence of chromatin architecture within a tight time window that coincides with the onset of transcription activation in the zygote. Prior to zygotic genome activation, the genome is mostly unstructured. Early expressed genes serve as nucleation sites for topologically associating domain (TAD) boundaries. Activation of gene expression coincides with the establishment of TADs throughout the genome and co-localization of housekeeping gene clusters, which remain stable in subsequent stages of development. However, the appearance of TAD boundaries is independent of transcription and requires the transcription factor Zelda for locus-specific TAD boundary insulation. These results offer insight into when spatial organization of the genome emerges and identify a key factor that helps trigger this architecture.
      Graphical abstract image Teaser Chromosome architecture gains complexity during development in concert with the onset of zygotic genome activation but without reliance on transcription.

      PubDate: 2017-04-10T01:41:43Z
       
  • Aneuploidy Causes Non-genetic Individuality
    • Abstract: Publication date: 6 April 2017
      Source:Cell, Volume 169, Issue 2
      Author(s): Rebecca R. Beach, Chiara Ricci-Tam, Christopher M. Brennan, Christine A. Moomau, Pei-hsin Hsu, Bo Hua, Rebecca E. Silberman, Michael Springer, Angelika Amon
      Phenotypic variability is a hallmark of diseases involving chromosome gains and losses, such as Down syndrome and cancer. Allelic variances have been thought to be the sole cause of this heterogeneity. Here, we systematically examine the consequences of gaining and losing single or multiple chromosomes to show that the aneuploid state causes non-genetic phenotypic variability. Yeast cell populations harboring the same defined aneuploidy exhibit heterogeneity in cell-cycle progression and response to environmental perturbations. Variability increases with degree of aneuploidy and is partly due to gene copy number imbalances, suggesting that subtle changes in gene expression impact the robustness of biological networks and cause alternate behaviors when they occur across many genes. As inbred trisomic mice also exhibit variable phenotypes, we further propose that non-genetic individuality is a universal characteristic of the aneuploid state that may contribute to variability in presentation and treatment responses of diseases caused by aneuploidy.
      Graphical abstract image Teaser Aneuploidy leads to phenotypic variability, even in cells that are karyotypically identical.

      PubDate: 2017-04-10T01:41:43Z
       
  • Derivation of Pluripotent Stem Cells with In Vivo Embryonic and
           Extraembryonic Potency
    • Abstract: Publication date: 6 April 2017
      Source:Cell, Volume 169, Issue 2
      Author(s): Yang Yang, Bei Liu, Jun Xu, Jinlin Wang, Jun Wu, Cheng Shi, Yaxing Xu, Jiebin Dong, Chengyan Wang, Weifeng Lai, Jialiang Zhu, Liang Xiong, Dicong Zhu, Xiang Li, Weifeng Yang, Takayoshi Yamauchi, Atsushi Sugawara, Zhongwei Li, Fangyuan Sun, Xiangyun Li, Chen Li, Aibin He, Yaqin Du, Ting Wang, Chaoran Zhao, Haibo Li, Xiaochun Chi, Hongquan Zhang, Yifang Liu, Cheng Li, Shuguang Duo, Ming Yin, Huan Shen, Juan Carlos Izpisua Belmonte, Hongkui Deng
      Of all known cultured stem cell types, pluripotent stem cells (PSCs) sit atop the landscape of developmental potency and are characterized by their ability to generate all cell types of an adult organism. However, PSCs show limited contribution to the extraembryonic placental tissues in vivo. Here, we show that a chemical cocktail enables the derivation of stem cells with unique functional and molecular features from mice and humans, designated as extended pluripotent stem (EPS) cells, which are capable of chimerizing both embryonic and extraembryonic tissues. Notably, a single mouse EPS cell shows widespread chimeric contribution to both embryonic and extraembryonic lineages in vivo and permits generating single-EPS-cell-derived mice by tetraploid complementation. Furthermore, human EPS cells exhibit interspecies chimeric competency in mouse conceptuses. Our findings constitute a first step toward capturing pluripotent stem cells with extraembryonic developmental potentials in culture and open new avenues for basic and translational research. Video
      Graphical abstract image Teaser Pluripotent stem cells in a defined chemical culture condition can generate both embryonic and extraembryonic tissues at the single-cell level.

      PubDate: 2017-04-10T01:41:43Z
       
  • Physiologic Medium Rewires Cellular Metabolism and Reveals Uric Acid as an
           Endogenous Inhibitor of UMP Synthase
    • Abstract: Publication date: 6 April 2017
      Source:Cell, Volume 169, Issue 2
      Author(s): Jason R. Cantor, Monther Abu-Remaileh, Naama Kanarek, Elizaveta Freinkman, Xin Gao, Abner Louissaint, Caroline A. Lewis, David M. Sabatini
      A complex interplay of environmental factors impacts the metabolism of human cells, but neither traditional culture media nor mouse plasma mimic the metabolite composition of human plasma. Here, we developed a culture medium with polar metabolite concentrations comparable to those of human plasma (human plasma-like medium [HPLM]). Culture in HPLM, relative to that in traditional media, had widespread effects on cellular metabolism, including on the metabolome, redox state, and glucose utilization. Among the most prominent was an inhibition of de novo pyrimidine synthesis—an effect traced to uric acid, which is 10-fold higher in the blood of humans than of mice and other non-primates. We find that uric acid directly inhibits uridine monophosphate synthase (UMPS) and consequently reduces the sensitivity of cancer cells to the chemotherapeutic agent 5-fluorouracil. Thus, media that better recapitulates the composition of human plasma reveals unforeseen metabolic wiring and regulation, suggesting that HPLM should be of broad utility.
      Graphical abstract image Teaser Mimicking the metabolite composition of human plasma in culture extensively alters the metabolic landscape of cells and highlights the potential to uncover new metabolite-drug interactions.

      PubDate: 2017-04-10T01:41:43Z
       
  • Architectures of Lipid Transport Systems for the Bacterial Outer Membrane
    • Abstract: Publication date: 6 April 2017
      Source:Cell, Volume 169, Issue 2
      Author(s): Damian C. Ekiert, Gira Bhabha, Georgia L. Isom, Garrett Greenan, Sergey Ovchinnikov, Ian R. Henderson, Jeffery S. Cox, Ronald D. Vale
      How phospholipids are trafficked between the bacterial inner and outer membranes through the hydrophilic space of the periplasm is not known. We report that members of the mammalian cell entry (MCE) protein family form hexameric assemblies with a central channel capable of mediating lipid transport. The E. coli MCE protein, MlaD, forms a ring associated with an ABC transporter complex in the inner membrane. A soluble lipid-binding protein, MlaC, ferries lipids between MlaD and an outer membrane protein complex. In contrast, EM structures of two other E. coli MCE proteins show that YebT forms an elongated tube consisting of seven stacked MCE rings, and PqiB adopts a syringe-like architecture. Both YebT and PqiB create channels of sufficient length to span the periplasmic space. This work reveals diverse architectures of highly conserved protein-based channels implicated in the transport of lipids between the membranes of bacteria and some eukaryotic organelles.
      Graphical abstract image Teaser A conserved structural building block is used to create a wide range of periplasm-spanning architectures implicated in lipid trafficking between the inner membrane and outer membrane in bacteria.

      PubDate: 2017-04-10T01:41:43Z
       
  • ESCRT-III Acts Downstream of MLKL to Regulate Necroptotic Cell Death and
           Its Consequences
    • Abstract: Publication date: 6 April 2017
      Source:Cell, Volume 169, Issue 2
      Author(s): Yi-Nan Gong, Cliff Guy, Hannes Olauson, Jan Ulrich Becker, Mao Yang, Patrick Fitzgerald, Andreas Linkermann, Douglas R. Green
      The activation of mixed lineage kinase-like (MLKL) by receptor-interacting protein kinase-3 (RIPK3) results in plasma membrane (PM) disruption and a form of regulated necrosis, called necroptosis. Here, we show that, during necroptosis, MLKL-dependent calcium (Ca2+) influx and phosphatidylserine (PS) exposure on the outer leaflet of the plasma membrane preceded loss of PM integrity. Activation of MLKL results in the generation of broken, PM “bubbles” with exposed PS that are released from the surface of the otherwise intact cell. The ESCRT-III machinery is required for formation of these bubbles and acts to sustain survival of the cell when MLKL activation is limited or reversed. Under conditions of necroptotic cell death, ESCRT-III controls the duration of plasma membrane integrity. As a consequence of the action of ESCRT-III, cells undergoing necroptosis can express chemokines and other regulatory molecules and promote antigenic cross-priming of CD8+ T cells.
      Graphical abstract image Teaser Cells undergoing necroptosis are not always headed towards death; ESCRT-III helps preserve the plasma membrane in these cells, contributing to survival.

      PubDate: 2017-04-10T01:41:43Z
       
  • Circulating Immune Cells Mediate a Systemic RNAi-Based Adaptive Antiviral
           Response in Drosophila
    • Abstract: Publication date: 6 April 2017
      Source:Cell, Volume 169, Issue 2
      Author(s): Michel Tassetto, Mark Kunitomi, Raul Andino
      Effective antiviral protection in multicellular organisms relies on both cell-autonomous and systemic immunity. Systemic immunity mediates the spread of antiviral signals from infection sites to distant uninfected tissues. In arthropods, RNA interference (RNAi) is responsible for antiviral defense. Here, we show that flies have a sophisticated systemic RNAi-based immunity mediated by macrophage-like haemocytes. Haemocytes take up dsRNA from infected cells and, through endogenous transposon reverse transcriptases, produce virus-derived complementary DNAs (vDNA). These vDNAs template de novo synthesis of secondary viral siRNAs (vsRNA), which are secreted in exosome-like vesicles. Strikingly, exosomes containing vsRNAs, purified from haemolymph of infected flies, confer passive protection against virus challenge in naive animals. Thus, similar to vertebrates, insects use immune cells to generate immunological memory in the form of stable vDNAs that generate systemic immunity, which is mediated by the vsRNA-containing exosomes.
      Graphical abstract image Teaser Drosophila, thought to lack an adaptive immune system, have dedicated immune cells that can alter their genetic repertoire to amplify and spread systemically antiviral RNAi signals to combat viral infection, providing protection to naive cells.

      PubDate: 2017-04-10T01:41:43Z
       
  • Transcription Impacts the Efficiency of mRNA Translation via
           Co-transcriptional N6-adenosine Methylation
    • Abstract: Publication date: 6 April 2017
      Source:Cell, Volume 169, Issue 2
      Author(s): Boris Slobodin, Ruiqi Han, Vittorio Calderone, Joachim A.F. Oude Vrielink, Fabricio Loayza-Puch, Ran Elkon, Reuven Agami
      Transcription and translation are two main pillars of gene expression. Due to the different timings, spots of action, and mechanisms of regulation, these processes are mainly regarded as distinct and generally uncoupled, despite serving a common purpose. Here, we sought for a possible connection between transcription and translation. Employing an unbiased screen of multiple human promoters, we identified a positive effect of TATA box on translation and a general coupling between mRNA expression and translational efficiency. Using a CRISPR-Cas9-mediated approach, genome-wide analyses, and in vitro experiments, we show that the rate of transcription regulates the efficiency of translation. Furthermore, we demonstrate that m6A modification of mRNAs is co-transcriptional and depends upon the dynamics of the transcribing RNAPII. Suboptimal transcription rates lead to elevated m6A content, which may result in reduced translation. This study uncovers a general and widespread link between transcription and translation that is governed by epigenetic modification of mRNAs.
      Graphical abstract image Teaser Slowly transcribed mRNAs show increased levels of N6-adenosine methylation and reduced translation efficiency, setting up a nuclear control on protein abundance.

      PubDate: 2017-04-10T01:41:43Z
       
  • Multidimensional Tracking of GPCR Signaling via Peroxidase-Catalyzed
           Proximity Labeling
    • Abstract: Publication date: 6 April 2017
      Source:Cell, Volume 169, Issue 2
      Author(s): Jaeho Paek, Marian Kalocsay, Dean P. Staus, Laura Wingler, Roberta Pascolutti, Joao A. Paulo, Steven P. Gygi, Andrew C. Kruse
      G-protein-coupled receptors (GPCRs) play critical roles in regulating physiological processes ranging from neurotransmission to cardiovascular function. Current methods for tracking GPCR signaling suffer from low throughput, modification or overexpression of effector proteins, and low temporal resolution. Here, we show that peroxidase-catalyzed proximity labeling can be combined with isobaric tagging and mass spectrometry to enable quantitative, time-resolved measurement of GPCR agonist response in living cells. Using this technique, termed “GPCR-APEX,” we track activation and internalization of the angiotensin II type 1 receptor and the β2 adrenoceptor. These receptors co-localize with a variety of G proteins even before receptor activation, and activated receptors are largely sequestered from G proteins upon internalization. Additionally, the two receptors show differing internalization kinetics, and we identify the membrane protein LMBRD2 as a potential regulator of β2 adrenoceptor signaling, underscoring the value of a dynamic view of receptor function.
      Graphical abstract image Teaser Using APEX proximity labeling to monitor GPCR signaling provides both spatial and temporal insight into receptor signaling and internalization in response to both balanced and biased GPCR ligands.

      PubDate: 2017-04-10T01:41:43Z
       
  • An Approach to Spatiotemporally Resolve Protein Interaction Networks in
           Living Cells
    • Abstract: Publication date: 6 April 2017
      Source:Cell, Volume 169, Issue 2
      Author(s): Braden T. Lobingier, Ruth Hüttenhain, Kelsie Eichel, Kenneth B. Miller, Alice Y. Ting, Mark von Zastrow, Nevan J. Krogan
      Cells operate through protein interaction networks organized in space and time. Here, we describe an approach to resolve both dimensions simultaneously by using proximity labeling mediated by engineered ascorbic acid peroxidase (APEX). APEX has been used to capture entire organelle proteomes with high temporal resolution, but its breadth of labeling is generally thought to preclude the higher spatial resolution necessary to interrogate specific protein networks. We provide a solution to this problem by combining quantitative proteomics with a system of spatial references. As proof of principle, we apply this approach to interrogate proteins engaged by G-protein-coupled receptors as they dynamically signal and traffic in response to ligand-induced activation. The method resolves known binding partners, as well as previously unidentified network components. Validating its utility as a discovery pipeline, we establish that two of these proteins promote ubiquitin-linked receptor downregulation after prolonged activation.
      Graphical abstract image Teaser Proximity labeling coupled with quantitative proteomics captures location and timing of GPCR function in live cells.

      PubDate: 2017-04-10T01:41:43Z
       
  • Inhibiting DNA Methylation Causes an Interferon Response in Cancer via
           dsRNA Including Endogenous Retroviruses
    • Abstract: Publication date: 6 April 2017
      Source:Cell, Volume 169, Issue 2
      Author(s): Katherine B. Chiappinelli, Pamela L. Strissel, Alexis Desrichard, Huili Li, Christine Henke, Benjamin Akman, Alexander Hein, Neal S. Rote, Leslie M. Cope, Alexandra Snyder, Vladimir Makarov, Sadna Budhu, Dennis J. Slamon, Jedd D. Wolchok, Drew M. Pardoll, Matthias W. Beckmann, Cynthia A. Zahnow, Taha Merghoub, Timothy A. Chan, Stephen B. Baylin, Reiner Strick


      PubDate: 2017-04-10T01:41:43Z
       
  • mTOR Signaling in Growth, Metabolism, and Disease
    • Abstract: Publication date: 6 April 2017
      Source:Cell, Volume 169, Issue 2
      Author(s): Robert A. Saxton, David M. Sabatini


      PubDate: 2017-04-10T01:41:43Z
       
  • RIPK3 Restricts Viral Pathogenesis via Cell Death-Independent
           Neuroinflammation
    • Abstract: Publication date: Available online 30 March 2017
      Source:Cell
      Author(s): Brian P. Daniels, Annelise G. Snyder, Tayla M. Olsen, Susana Orozco, Thomas H. Oguin, Stephen W.G. Tait, Jennifer Martinez, Michael Gale, Yueh-Ming Loo, Andrew Oberst
      Receptor-interacting protein kinase-3 (RIPK3) is an activator of necroptotic cell death, but recent work has implicated additional roles for RIPK3 in inflammatory signaling independent of cell death. However, while necroptosis has been shown to contribute to antiviral immunity, death-independent roles for RIPK3 in host defense have not been demonstrated. Using a mouse model of West Nile virus (WNV) encephalitis, we show that RIPK3 restricts WNV pathogenesis independently of cell death. Ripk3 −/− mice exhibited enhanced mortality compared to wild-type (WT) controls, while mice lacking the necroptotic effector MLKL, or both MLKL and caspase-8, were unaffected. The enhanced susceptibility of Ripk3 −/− mice arose from suppressed neuronal chemokine expression and decreased central nervous system (CNS) recruitment of T lymphocytes and inflammatory myeloid cells, while peripheral immunity remained intact. These data identify pleiotropic functions for RIPK3 in the restriction of viral pathogenesis and implicate RIPK3 as a key coordinator of immune responses within the CNS.
      Graphical abstract image Teaser Kinases associated with necroptotic cell death have a death-independent function, promoting neuroinflammation in the central nervous system during West Nile virus infection.

      PubDate: 2017-04-03T08:01:54Z
       
  • Experimental Evolution to Study Virus Emergence
    • Abstract: Publication date: 23 March 2017
      Source:Cell, Volume 169, Issue 1
      Author(s): Nathan D. Grubaugh, Kristian G. Andersen
      Understanding how viruses adapt to new environments and acquire new phenotypes is critical for developing comprehensive responses to outbreaks. By studying the emergence of vaccine-derived poliovirus outbreaks, Stern et al. describe how a combination of sequence analysis and experimental evolution can be used to reveal adaptive pathways.
      Teaser Understanding how viruses adapt to new environments and acquire new phenotypes is critical for developing comprehensive responses to outbreaks. By studying the emergence of vaccine-derived poliovirus outbreaks, Stern et al. describe how a combination of sequence analysis and experimental evolution can be used to reveal adaptive pathways.

      PubDate: 2017-03-27T09:31:43Z
       
  • Rejuvenation by Therapeutic Elimination of Senescent Cells
    • Abstract: Publication date: 23 March 2017
      Source:Cell, Volume 169, Issue 1
      Author(s): Paul Krimpenfort, Anton Berns
      In this issue of Cell, Baar et al. show how FOXO4 protects senescent cell viability by keeping p53 sequestered in nuclear bodies, preventing it from inducing apoptosis. Disrupting this interaction with an all-D amino acid peptide (FOXO4-DRI) restores p53’s apoptotic role and ameliorates the consequences of senescence-associated loss of tissue homeostasis.
      Teaser In this issue of Cell, Baar et al. show how FOXO4 protects senescent cell viability by keeping p53 sequestered in nuclear bodies, preventing it from inducing apoptosis. Disrupting this interaction with an all-D amino acid peptide (FOXO4-DRI) restores p53’s apoptotic role and ameliorates the consequences of senescence-associated loss of tissue homeostasis.

      PubDate: 2017-03-27T09:31:43Z
       
  • Bedside Back to Bench: Building Bridges between Basic and Clinical Genomic
           Research
    • Abstract: Publication date: 23 March 2017
      Source:Cell, Volume 169, Issue 1
      Author(s): Teri A. Manolio, Douglas M. Fowler, Lea M. Starita, Melissa A. Haendel, Daniel G. MacArthur, Leslie G. Biesecker, Elizabeth Worthey, Rex L. Chisholm, Eric D. Green, Howard J. Jacob, Howard L. McLeod, Dan Roden, Laura Lyman Rodriguez, Marc S. Williams, Gregory M. Cooper, Nancy J. Cox, Gail E. Herman, Stephen Kingsmore, Cecilia Lo, Cathleen Lutz, Calum A. MacRae, Robert L. Nussbaum, Jose M. Ordovas, Erin M. Ramos, Peter N. Robinson, Wendy S. Rubinstein, Christine Seidman, Barbara E. Stranger, Haoyi Wang, Monte Westerfield, Carol Bult
      Genome sequencing has revolutionized the diagnosis of genetic diseases. Close collaborations between basic scientists and clinical genomicists are now needed to link genetic variants with disease causation. To facilitate such collaborations, we recommend prioritizing clinically relevant genes for functional studies, developing reference variant-phenotype databases, adopting phenotype description standards, and promoting data sharing.
      Teaser Genome sequencing has revolutionized the diagnosis of genetic diseases. Close collaborations between basic scientists and clinical genomicists are now needed to link genetic variants with disease causation. To facilitate such collaborations, we recommend prioritizing clinically relevant genes for functional studies, developing reference variant-phenotype databases, adopting phenotype description standards, and promoting data sharing.

      PubDate: 2017-03-27T09:31:43Z
       
  • A Phase Separation Model for Transcriptional Control
    • Abstract: Publication date: 23 March 2017
      Source:Cell, Volume 169, Issue 1
      Author(s): Denes Hnisz, Krishna Shrinivas, Richard A. Young, Arup K. Chakraborty, Phillip A. Sharp
      Phase-separated multi-molecular assemblies provide a general regulatory mechanism to compartmentalize biochemical reactions within cells. We propose that a phase separation model explains established and recently described features of transcriptional control. These features include the formation of super-enhancers, the sensitivity of super-enhancers to perturbation, the transcriptional bursting patterns of enhancers, and the ability of an enhancer to produce simultaneous activation at multiple genes. This model provides a conceptual framework to further explore principles of gene control in mammals.
      Teaser A phase separation model for transcription explains key features of transcription and sets enhancers, and especially super-enhancers, into the broad family of membraneless organelles.

      PubDate: 2017-03-27T09:31:43Z
       
  • The Upsides and Downsides of Organelle Interconnectivity
    • Abstract: Publication date: 23 March 2017
      Source:Cell, Volume 169, Issue 1
      Author(s): Daniel E. Gottschling, Thomas Nyström
      Interconnectivity and feedback control are hallmarks of biological systems. This includes communication between organelles, which allows them to function and adapt to changing cellular environments. While the specific mechanisms for all communications remain opaque, unraveling the wiring of organelle networks is critical to understand how biological systems are built and why they might collapse, as occurs in aging. A comprehensive understanding of all the routes involved in inter-organelle communication is still lacking, but important themes are beginning to emerge, primarily in budding yeast. These routes are reviewed here in the context of sub-system proteostasis and complex adaptive systems theory.
      Teaser The communication between cellular organelles is important for basic cellular function. Mapping the wiring between organelle networks can reveal how and when a collapse in communication may occur, such as aging.

      PubDate: 2017-03-27T09:31:43Z
       
  • The Evolutionary Pathway to Virulence of an RNA Virus
    • Abstract: Publication date: 23 March 2017
      Source:Cell, Volume 169, Issue 1
      Author(s): Adi Stern, Ming Te Yeh, Tal Zinger, Matt Smith, Caroline Wright, Guy Ling, Rasmus Nielsen, Andrew Macadam, Raul Andino
      Paralytic polio once afflicted almost half a million children each year. The attenuated oral polio vaccine (OPV) has enabled world-wide vaccination efforts, which resulted in nearly complete control of the disease. However, poliovirus eradication is hampered globally by epidemics of vaccine-derived polio. Here, we describe a combined theoretical and experimental strategy that describes the molecular events leading from OPV to virulent strains. We discover that similar evolutionary events occur in most epidemics. The mutations and the evolutionary trajectories driving these epidemics are replicated using a simple cell-based experimental setup where the rate of evolution is intentionally accelerated. Furthermore, mutations accumulating during epidemics increase the replication fitness of the virus in cell culture and increase virulence in an animal model. Our study uncovers the evolutionary strategies by which vaccine strains become pathogenic and provides a powerful framework for rational design of safer vaccine strains and for forecasting virulence of viruses. Video
      Graphical abstract image Teaser Understanding how an attenuated strain of polio evolved to become fully virulent provides a new framework for rational design of safer vaccines.

      PubDate: 2017-03-27T09:31:43Z
       
  • Structure Reveals Mechanisms of Viral Suppressors that Intercept a CRISPR
           RNA-Guided Surveillance Complex
    • Abstract: Publication date: 23 March 2017
      Source:Cell, Volume 169, Issue 1
      Author(s): Saikat Chowdhury, Joshua Carter, MaryClare F. Rollins, Sarah M. Golden, Ryan N. Jackson, Connor Hoffmann, Lyn’Al Nosaka, Joseph Bondy-Denomy, Karen L. Maxwell, Alan R. Davidson, Elizabeth R. Fischer, Gabriel C. Lander, Blake Wiedenheft
      Genetic conflict between viruses and their hosts drives evolution and genetic innovation. Prokaryotes evolved CRISPR-mediated adaptive immune systems for protection from viral infection, and viruses have evolved diverse anti-CRISPR (Acr) proteins that subvert these immune systems. The adaptive immune system in Pseudomonas aeruginosa (type I-F) relies on a 350 kDa CRISPR RNA (crRNA)-guided surveillance complex (Csy complex) to bind foreign DNA and recruit a trans-acting nuclease for target degradation. Here, we report the cryo-electron microscopy (cryo-EM) structure of the Csy complex bound to two different Acr proteins, AcrF1 and AcrF2, at an average resolution of 3.4 Å. The structure explains the molecular mechanism for immune system suppression, and structure-guided mutations show that the Acr proteins bind to residues essential for crRNA-mediated detection of DNA. Collectively, these data provide a snapshot of an ongoing molecular arms race between viral suppressors and the immune system they target.
      Graphical abstract image Teaser The high-resolution structures of a CRISPR surveillance complex with two viral anti-CRISPR proteins reveal different strategies for silencing CRISPR immune function.

      PubDate: 2017-03-27T09:31:43Z
       
  • A Viral Immunoevasin Controls Innate Immunity by Targeting the
           Prototypical Natural Killer Cell Receptor Family
    • Abstract: Publication date: 23 March 2017
      Source:Cell, Volume 169, Issue 1
      Author(s): Oscar A. Aguilar, Richard Berry, Mir Munir A. Rahim, Johanna J. Reichel, Branka Popović, Miho Tanaka, Zhihui Fu, Gautham R. Balaji, Timothy N.H. Lau, Megan M. Tu, Christina L. Kirkham, Ahmad Bakur Mahmoud, Aruz Mesci, Astrid Krmpotić, David S.J. Allan, Andrew P. Makrigiannis, Stipan Jonjić, Jamie Rossjohn, James R. Carlyle
      Natural killer (NK) cells play a key role in innate immunity by detecting alterations in self and non-self ligands via paired NK cell receptors (NKRs). Despite identification of numerous NKR-ligand interactions, physiological ligands for the prototypical NK1.1 orphan receptor remain elusive. Here, we identify a viral ligand for the inhibitory and activating NKR-P1 (NK1.1) receptors. This murine cytomegalovirus (MCMV)-encoded protein, m12, restrains NK cell effector function by directly engaging the inhibitory NKR-P1B receptor. However, m12 also interacts with the activating NKR-P1A/C receptors to counterbalance m12 decoy function. Structural analyses reveal that m12 sequesters a large NKR-P1 surface area via a “polar claw” mechanism. Polymorphisms in, and ablation of, the viral m12 protein and host NKR-P1B/C alleles impact NK cell responses in vivo. Thus, we identify the long-sought foreign ligand for this key immunoregulatory NKR family and reveal how it controls the evolutionary balance of immune recognition during host-pathogen interplay.
      Graphical abstract image Teaser A viral decoy is the long-sought ligand for a key immunoregulatory receptor family on natural killer cells.

      PubDate: 2017-03-27T09:31:43Z
       
  • Human Epistatic Interaction Controls IL7R Splicing and Increases Multiple
           Sclerosis Risk
    • Abstract: Publication date: 23 March 2017
      Source:Cell, Volume 169, Issue 1
      Author(s): Gaddiel Galarza-Muñoz, Farren B.S. Briggs, Irina Evsyukova, Geraldine Schott-Lerner, Edward M. Kennedy, Tinashe Nyanhete, Liuyang Wang, Laura Bergamaschi, Steven G. Widen, Georgia D. Tomaras, Dennis C. Ko, Shelton S. Bradrick, Lisa F. Barcellos, Simon G. Gregory, Mariano A. Garcia-Blanco
      Multiple sclerosis (MS) is an autoimmune disorder where T cells attack neurons in the central nervous system (CNS) leading to demyelination and neurological deficits. A driver of increased MS risk is the soluble form of the interleukin-7 receptor alpha chain gene (sIL7R) produced by alternative splicing of IL7R exon 6. Here, we identified the RNA helicase DDX39B as a potent activator of this exon and consequently a repressor of sIL7R, and we found strong genetic association of DDX39B with MS risk. Indeed, we showed that a genetic variant in the 5′ UTR of DDX39B reduces translation of DDX39B mRNAs and increases MS risk. Importantly, this DDX39B variant showed strong genetic and functional epistasis with allelic variants in IL7R exon 6. This study establishes the occurrence of biological epistasis in humans and provides mechanistic insight into the regulation of IL7R exon 6 splicing and its impact on MS risk.
      Graphical abstract image Teaser Two genes interact epistatically in multiple sclerosis risk in humans.

      PubDate: 2017-03-27T09:31:43Z
       
 
 
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