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Journal Cover Cell
  [SJR: 28.188]   [H-I: 616]   [778 followers]  Follow
    
   Full-text available via subscription Subscription journal
   ISSN (Print) 0092-8674 - ISSN (Online) 1097-4172
   Published by Elsevier Homepage  [3042 journals]
  • Life-Long Genetic and Functional Access to Neural Circuits Using
           Self-Inactivating Rabies Virus
    • Abstract: Publication date: Available online 6 July 2017
      Source:Cell
      Author(s): Ernesto Ciabatti, Ana González-Rueda, Letizia Mariotti, Fabio Morgese, Marco Tripodi
      Neural networks are emerging as the fundamental computational unit of the brain and it is becoming progressively clearer that network dysfunction is at the core of a number of psychiatric and neurodegenerative disorders. Yet, our ability to target specific networks for functional or genetic manipulations remains limited. Monosynaptically restricted rabies virus facilitates the anatomical investigation of neural circuits. However, the inherent cytotoxicity of the rabies largely prevents its implementation in long-term functional studies and the genetic manipulation of neural networks. To overcome this limitation, we developed a self-inactivating ΔG-rabies virus (SiR) that transcriptionally disappears from the infected neurons while leaving permanent genetic access to the traced network. SiR provides a virtually unlimited temporal window for the study of network dynamics and for the genetic and functional manipulation of neural circuits in vivo without adverse effects on neuronal physiology and circuit function.
      Graphical abstract image Teaser A self-inactivating rabies virus provides a virtually unlimited temporal window for the study and manipulation of neural circuits in vivo without adverse effects on neuronal physiology and circuit function.

      PubDate: 2017-07-09T17:13:01Z
       
  • Distinct Ventral Pallidal Neural Populations Mediate Separate Symptoms of
           Depression
    • Abstract: Publication date: Available online 6 July 2017
      Source:Cell
      Author(s): Daniel Knowland, Varoth Lilascharoen, Christopher Pham Pacia, Sora Shin, Eric Hou-Jen Wang, Byung Kook Lim
      Major depressive disorder (MDD) patients display a common but often variable set of symptoms making successful, sustained treatment difficult to achieve. Separate depressive symptoms may be encoded by differential changes in distinct circuits in the brain, yet how discrete circuits underlie behavioral subsets of depression and how they adapt in response to stress has not been addressed. We identify two discrete circuits of parvalbumin-positive (PV) neurons in the ventral pallidum (VP) projecting to either the lateral habenula or ventral tegmental area contributing to depression. We find that these populations undergo different electrophysiological adaptations in response to social defeat stress, which are normalized by antidepressant treatment. Furthermore, manipulation of each population mediates either social withdrawal or behavioral despair, but not both. We propose that distinct components of the VP PV circuit can subserve related, yet separate depressive-like phenotypes in mice, which could ultimately provide a platform for symptom-specific treatments of depression.
      Graphical abstract image Teaser Distinct symptoms of depression are encoded in discrete circuits of the ventral pallidum that project to separate brain regions contributing to depression.

      PubDate: 2017-07-09T17:13:01Z
       
  • One (Cell) in a Million
    • Abstract: Publication date: 29 June 2017
      Source:Cell, Volume 170, Issue 1
      Author(s): Matthew Pavlovich


      PubDate: 2017-07-09T17:13:01Z
       
  • Splicing-Correcting Therapy for SMA
    • Abstract: Publication date: 29 June 2017
      Source:Cell, Volume 170, Issue 1
      Author(s): Lili Wan, Gideon Dreyfuss
      Spinal muscular atrophy (SMA) is caused by deficiency of SMN protein, which is crucial for spliceosome subunits biogenesis. Most SMA patients have SMN1 deletions, leaving SMN2 as sole SMN source; however, a C→T substitution converts an exonic-splicing enhancer (ESE) to a silencer (ESS), causing frequent exon7 skipping in SMN2 pre-mRNA and yielding a truncated protein. Antisense treatment to SMN2 intron7-splicing silencer (ISS) improves SMN expression and motor function. To view this Bench to Bedside, open or download the PDF.
      Teaser Spinal muscular atrophy (SMA) is caused by deficiency of SMN protein, which is crucial for spliceosome subunits biogenesis. Most SMA patients have SMN1 deletions, leaving SMN2 as sole SMN source; however, a C→T substitution converts an exonic-splicing enhancer (ESE) to a silencer (ESS), causing frequent exon7 skipping in SMN2 pre-mRNA and yielding a truncated protein. Antisense treatment to SMN2 intron7-splicing silencer (ISS) improves SMN expression and motor function. To view this Bench to Bedside, open or download the PDF.

      PubDate: 2017-07-09T17:13:01Z
       
  • What Is the Future of Developmental Biology'
    • Abstract: Publication date: 29 June 2017
      Source:Cell, Volume 170, Issue 1


      PubDate: 2017-07-09T17:13:01Z
       
  • Approaching TERRA Firma: Genomic Functions of Telomeric Noncoding RNA
    • Abstract: Publication date: 29 June 2017
      Source:Cell, Volume 170, Issue 1
      Author(s): Caitlin M. Roake, Steven E. Artandi
      Functions of the telomeric repeat-containing RNA (TERRA), the long noncoding RNA (lncRNA) transcribed from telomeres, have eluded researchers. In this issue of Cell, Graf el al. and Chu et al. uncover new regulatory roles for TERRA at the telomere and at distant genomic sites.
      Teaser Functions of the telomeric repeat-containing RNA (TERRA), the long noncoding RNA (lncRNA) transcribed from telomeres, have eluded researchers. In this issue of Cell, Graf el al. and Chu et al. uncover new regulatory roles for TERRA at the telomere and at distant genomic sites.

      PubDate: 2017-07-09T17:13:01Z
       
  • How the Gut Feels, Smells, and Talks
    • Abstract: Publication date: 29 June 2017
      Source:Cell, Volume 170, Issue 1
      Author(s): Joep Beumer, Hans Clevers
      Gut-brain signaling plays a central role in a range of homeostatic processes, yet details of this cross-talk remain enigmatic. In this issue of Cell, Bellono and colleagues identify a variety of luminal stimuli acting on serotonin-secreting enteroendocrine cells and, for the first time, demonstrate a functional synaptic interaction with neurons.
      Teaser Gut-brain signaling plays a central role in a range of homeostatic processes, yet details of this cross-talk remain enigmatic. In this issue of Cell, Bellono and colleagues identify a variety of luminal stimuli acting on serotonin-secreting enteroendocrine cells and, for the first time, demonstrate a functional synaptic interaction with neurons.

      PubDate: 2017-07-09T17:13:01Z
       
  • A New Drug Target for Type 2 Diabetes
    • Abstract: Publication date: 29 June 2017
      Source:Cell, Volume 170, Issue 1
      Author(s): Lukas K.J. Stadler, I. Sadaf Farooqi
      Genetic studies can identify novel therapeutic targets for common complex diseases. In this issue of Cell, Rusu et al. demonstrate that a cluster of genetic variants associated with an increased risk of type 2 diabetes affect the function of a monocarboxylate transporter involved in nutrient flux and hepatic lipid metabolism.
      Teaser Genetic studies can identify novel therapeutic targets for common complex diseases. In this issue of Cell, Rusu et al. demonstrate that a cluster of genetic variants associated with an increased risk of type 2 diabetes affect the function of a monocarboxylate transporter involved in nutrient flux and hepatic lipid metabolism.

      PubDate: 2017-07-09T17:13:01Z
       
  • Friction at the BAR Leads to Membrane Breakup
    • Abstract: Publication date: 29 June 2017
      Source:Cell, Volume 170, Issue 1
      Author(s): Kranthi K. Mandadapu, James H. Hurley
      A long-standing question in cell biology is how endocytic vesicles and tubules detach from the plasma membrane in the absence of constriction by dynamin. In this issue of Cell, Simunovic et al. describe an elegant biophysical model in which friction between lipids and BAR-domain proteins drives the scission of elongating membrane tubules.
      Teaser A long-standing question in cell biology is how endocytic vesicles and tubules detach from the plasma membrane in the absence of constriction by dynamin. In this issue of Cell, Simunovic et al. describe an elegant biophysical model in which friction between lipids and BAR-domain proteins drives the scission of elongating membrane tubules.

      PubDate: 2017-07-09T17:13:01Z
       
  • RAS Proteins and Their Regulators in Human Disease
    • Abstract: Publication date: 29 June 2017
      Source:Cell, Volume 170, Issue 1
      Author(s): Dhirendra K. Simanshu, Dwight V. Nissley, Frank McCormick
      RAS proteins are binary switches, cycling between ON and OFF states during signal transduction. These switches are normally tightly controlled, but in RAS-related diseases, such as cancer, RASopathies, and many psychiatric disorders, mutations in the RAS genes or their regulators render RAS proteins persistently active. The structural basis of the switch and many of the pathways that RAS controls are well known, but the precise mechanisms by which RAS proteins function are less clear. All RAS biology occurs in membranes: a precise understanding of RAS’ interaction with membranes is essential to understand RAS action and to intervene in RAS-driven diseases.
      Teaser RAS proteins have been linked to several cancers. The identification of RAS regulatory proteins has provided deeper insights into the biochemical and biophysical properties of RAS proteins as well as shed light into ways to target them pharmacologically.

      PubDate: 2017-07-09T17:13:01Z
       
  • Massively Parallel Biophysical Analysis of CRISPR-Cas Complexes on Next
           Generation Sequencing Chips
    • Abstract: Publication date: 29 June 2017
      Source:Cell, Volume 170, Issue 1
      Author(s): Cheulhee Jung, John A. Hawkins, Stephen K. Jones, Yibei Xiao, James R. Rybarski, Kaylee E. Dillard, Jeffrey Hussmann, Fatema A. Saifuddin, Cagri A. Savran, Andrew D. Ellington, Ailong Ke, William H. Press, Ilya J. Finkelstein
      CRISPR-Cas nucleoproteins target foreign DNA via base pairing with a crRNA. However, a quantitative description of protein binding and nuclease activation at off-target DNA sequences remains elusive. Here, we describe a chip-hybridized association-mapping platform (CHAMP) that repurposes next-generation sequencing chips to simultaneously measure the interactions between proteins and ∼107 unique DNA sequences. Using CHAMP, we provide the first comprehensive survey of DNA recognition by a type I-E CRISPR-Cas (Cascade) complex and Cas3 nuclease. Analysis of mutated target sequences and human genomic DNA reveal that Cascade recognizes an extended protospacer adjacent motif (PAM). Cascade recognizes DNA with a surprising 3-nt periodicity. The identity of the PAM and the PAM-proximal nucleotides control Cas3 recruitment by releasing the Cse1 subunit. These findings are used to develop a model for the biophysical constraints governing off-target DNA binding. CHAMP provides a framework for high-throughput, quantitative analysis of protein-DNA interactions on synthetic and genomic DNA. PaperClip
      Graphical abstract image Teaser Discarded next-gen sequencing chips provide a platform for analyzing protein-DNA interactions that reveals a novel proofreading mechanism used by the Cascade/Cas3 complex.

      PubDate: 2017-07-09T17:13:01Z
       
  • Structure Basis for Directional R-loop Formation and Substrate Handover
           Mechanisms in Type I CRISPR-Cas System
    • Abstract: Publication date: 29 June 2017
      Source:Cell, Volume 170, Issue 1
      Author(s): Yibei Xiao, Min Luo, Robert P. Hayes, Jonathan Kim, Sherwin Ng, Fang Ding, Maofu Liao, Ailong Ke
      Type I CRISPR systems feature a sequential dsDNA target searching and degradation process, by crRNA-displaying Cascade and nuclease-helicase fusion enzyme Cas3, respectively. Here we present two cryo-EM snapshots of the Thermobifida fusca type I-E Cascade: (1) unwinding 11 bp of dsDNA at the seed-sequence region to scout for sequence complementarity, and (2) further unwinding of the entire protospacer to form a full R-loop. These structures provide the much-needed temporal and spatial resolution to resolve key mechanistic steps leading to Cas3 recruitment. In the early steps, PAM recognition causes severe DNA bending, leading to spontaneous DNA unwinding to form a seed-bubble. The full R-loop formation triggers conformational changes in Cascade, licensing Cas3 to bind. The same process also generates a bulge in the non-target DNA strand, enabling its handover to Cas3 for cleavage. The combination of both negative and positive checkpoints ensures stringent yet efficient target degradation in type I CRISPR-Cas systems.
      Graphical abstract image Teaser Cryo-EM structures of type I CRISPR-Cas system resolve the mechanisms governing the PAM-dependent R-loop formation, Cas3 recruitment, and substrate handover processes.

      PubDate: 2017-07-09T17:13:01Z
       
  • LTR-Retrotransposon Control by tRNA-Derived Small RNAs
    • Abstract: Publication date: 29 June 2017
      Source:Cell, Volume 170, Issue 1
      Author(s): Andrea J. Schorn, Michael J. Gutbrod, Chantal LeBlanc, Rob Martienssen
      Transposon reactivation is an inherent danger in cells that lose epigenetic silencing during developmental reprogramming. In the mouse, long terminal repeat (LTR)-retrotransposons, or endogenous retroviruses (ERV), account for most novel insertions and are expressed in the absence of histone H3 lysine 9 trimethylation in preimplantation stem cells. We found abundant 18 nt tRNA-derived small RNA (tRF) in these cells and ubiquitously expressed 22 nt tRFs that include the 3′ terminal CCA of mature tRNAs and target the tRNA primer binding site (PBS) essential for ERV reverse transcription. We show that the two most active ERV families, IAP and MusD/ETn, are major targets and are strongly inhibited by tRFs in retrotransposition assays. 22 nt tRFs post-transcriptionally silence coding-competent ERVs, while 18 nt tRFs specifically interfere with reverse transcription and retrotransposon mobility. The PBS offers a unique target to specifically inhibit LTR-retrotransposons, and tRF-targeting is a potentially highly conserved mechanism of small RNA–mediated transposon control.
      Graphical abstract image Teaser 3′ tRNA fragments limit the mobility of transposable elements in mammalian cells.

      PubDate: 2017-07-09T17:13:01Z
       
  • Telomere Length Determines TERRA and R-Loop Regulation through the Cell
           Cycle
    • Abstract: Publication date: 29 June 2017
      Source:Cell, Volume 170, Issue 1
      Author(s): Marco Graf, Diego Bonetti, Arianna Lockhart, Kamar Serhal, Vanessa Kellner, André Maicher, Pascale Jolivet, Maria Teresa Teixeira, Brian Luke
      Maintenance of a minimal telomere length is essential to prevent cellular senescence. When critically short telomeres arise in the absence of telomerase, they can be repaired by homology-directed repair (HDR) to prevent premature senescence onset. It is unclear why specifically the shortest telomeres are targeted for HDR. We demonstrate that the non-coding RNA TERRA accumulates as HDR-promoting RNA-DNA hybrids (R-loops) preferentially at very short telomeres. The increased level of TERRA and R-loops, exclusively at short telomeres, is due to a local defect in RNA degradation by the Rat1 and RNase H2 nucleases, respectively. Consequently, the coordination of TERRA degradation with telomere replication is altered at shortened telomeres. R-loop persistence at short telomeres contributes to activation of the DNA damage response (DDR) and promotes recruitment of the Rad51 recombinase. Thus, the telomere length-dependent regulation of TERRA and TERRA R-loops is a critical determinant of the rate of replicative senescence.
      Graphical abstract image Teaser TERRA balances repair mechanisms at short telomeres to preserve genome integrity.

      PubDate: 2017-07-09T17:13:01Z
       
  • TERRA RNA Antagonizes ATRX and Protects Telomeres
    • Abstract: Publication date: 29 June 2017
      Source:Cell, Volume 170, Issue 1
      Author(s): Hsueh-Ping Chu, Catherine Cifuentes-Rojas, Barry Kesner, Eric Aeby, Hun-goo Lee, Chunyao Wei, Hyun Jung Oh, Myriam Boukhali, Wilhelm Haas, Jeannie T. Lee
      Through an integration of genomic and proteomic approaches to advance understanding of long noncoding RNAs, we investigate the function of the telomeric transcript, TERRA. By identifying thousands of TERRA target sites in the mouse genome, we demonstrate that TERRA can bind both in cis to telomeres and in trans to genic targets. We then define a large network of interacting proteins, including epigenetic factors, telomeric proteins, and the RNA helicase, ATRX. TERRA and ATRX share hundreds of target genes and are functionally antagonistic at these loci: whereas TERRA activates, ATRX represses gene expression. At telomeres, TERRA competes with telomeric DNA for ATRX binding, suppresses ATRX localization, and ensures telomeric stability. Depleting TERRA increases telomerase activity and induces telomeric pathologies, including formation of telomere-induced DNA damage foci and loss or duplication of telomeric sequences. We conclude that TERRA functions as an epigenomic modulator in trans and as an essential regulator of telomeres in cis.
      Graphical abstract image Teaser The functions of the long noncoding RNA TERRA are revealed through a combination of genomic and proteomic approaches, and the helicase ATRX is an important binding partner for its ability to regulate telomere function.

      PubDate: 2017-07-09T17:13:01Z
       
  • A Natural Allele of a Transcription Factor in Rice Confers Broad-Spectrum
           Blast Resistance
    • Abstract: Publication date: 29 June 2017
      Source:Cell, Volume 170, Issue 1
      Author(s): Weitao Li, Ziwei Zhu, Mawsheng Chern, Junjie Yin, Chao Yang, Li Ran, Mengping Cheng, Min He, Kang Wang, Jing Wang, Xiaogang Zhou, Xiaobo Zhu, Zhixiong Chen, Jichun Wang, Wen Zhao, Bingtian Ma, Peng Qin, Weilan Chen, Yuping Wang, Jiali Liu, Wenming Wang, Xianjun Wu, Ping Li, Jirui Wang, Lihuang Zhu, Shigui Li, Xuewei Chen
      Rice feeds half the world’s population, and rice blast is often a destructive disease that results in significant crop loss. Non-race-specific resistance has been more effective in controlling crop diseases than race-specific resistance because of its broad spectrum and durability. Through a genome-wide association study, we report the identification of a natural allele of a C2H2-type transcription factor in rice that confers non-race-specific resistance to blast. A survey of 3,000 sequenced rice genomes reveals that this allele exists in 10% of rice, suggesting that this favorable trait has been selected through breeding. This allele causes a single nucleotide change in the promoter of the bsr-d1 gene, which results in reduced expression of the gene through the binding of the repressive MYB transcription factor and, consequently, an inhibition of H2O2 degradation and enhanced disease resistance. Our discovery highlights this novel allele as a strategy for breeding durable resistance in rice.
      Graphical abstract image Teaser A natural allele of a C2H2-domain transcription factor gene, bsr-d1, confers broad-spectrum resistance to rice blast.

      PubDate: 2017-07-09T17:13:01Z
       
  • IFNγ-Dependent Tissue-Immune Homeostasis Is Co-opted in the Tumor
           Microenvironment
    • Abstract: Publication date: 29 June 2017
      Source:Cell, Volume 170, Issue 1
      Author(s): Christopher J. Nirschl, Mayte Suárez-Fariñas, Benjamin Izar, Sanjay Prakadan, Ruth Dannenfelser, Itay Tirosh, Yong Liu, Qian Zhu, K. Sanjana P. Devi, Shaina L. Carroll, David Chau, Melika Rezaee, Tae-Gyun Kim, Ruiqi Huang, Judilyn Fuentes-Duculan, George X. Song-Zhao, Nicholas Gulati, Michelle A. Lowes, Sandra L. King, Francisco J. Quintana, Young-suk Lee, James G. Krueger, Kavita Y. Sarin, Charles H. Yoon, Levi Garraway, Aviv Regev, Alex K. Shalek, Olga Troyanskaya, Niroshana Anandasabapathy
      Homeostatic programs balance immune protection and self-tolerance. Such mechanisms likely impact autoimmunity and tumor formation, respectively. How homeostasis is maintained and impacts tumor surveillance is unknown. Here, we find that different immune mononuclear phagocytes share a conserved steady-state program during differentiation and entry into healthy tissue. IFNγ is necessary and sufficient to induce this program, revealing a key instructive role. Remarkably, homeostatic and IFNγ-dependent programs enrich across primary human tumors, including melanoma, and stratify survival. Single-cell RNA sequencing (RNA-seq) reveals enrichment of homeostatic modules in monocytes and DCs from human metastatic melanoma. Suppressor-of-cytokine-2 (SOCS2) protein, a conserved program transcript, is expressed by mononuclear phagocytes infiltrating primary melanoma and is induced by IFNγ. SOCS2 limits adaptive anti-tumoral immunity and DC-based priming of T cells in vivo, indicating a critical regulatory role. These findings link immune homeostasis to key determinants of anti-tumoral immunity and escape, revealing co-opting of tissue-specific immune development in the tumor microenvironment.
      Graphical abstract image Teaser Tumors exploit physiological mechanisms that are in place to keep tissue homeostasis in order to escape the surveillance of the immune system.

      PubDate: 2017-07-09T17:13:01Z
       
  • Complement-Related Regulates Autophagy in Neighboring Cells
    • Abstract: Publication date: 29 June 2017
      Source:Cell, Volume 170, Issue 1
      Author(s): Lin Lin, Frederico S.L.M. Rodrigues, Christina Kary, Alicia Contet, Mary Logan, Richard H.G. Baxter, Will Wood, Eric H. Baehrecke
      Autophagy degrades cytoplasmic components and is important for development and human health. Although autophagy is known to be influenced by systemic intercellular signals, the proteins that control autophagy are largely thought to function within individual cells. Here, we report that Drosophila macroglobulin complement-related (Mcr), a complement ortholog, plays an essential role during developmental cell death and inflammation by influencing autophagy in neighboring cells. This function of Mcr involves the immune receptor Draper, suggesting a relationship between autophagy and the control of inflammation. Interestingly, Mcr function in epithelial cells is required for macrophage autophagy and migration to epithelial wounds, a Draper-dependent process. This study reveals, unexpectedly, that complement-related from one cell regulates autophagy in neighboring cells via an ancient immune signaling program.
      Graphical abstract image Teaser A complement ortholog in Drosophila plays an essential role during developmental cell death and inflammation by influencing autophagy in neighboring cells.

      PubDate: 2017-07-09T17:13:01Z
       
  • Type 2 Diabetes Variants Disrupt Function of SLC16A11 through Two Distinct
           Mechanisms
    • Abstract: Publication date: 29 June 2017
      Source:Cell, Volume 170, Issue 1
      Author(s): Victor Rusu, Eitan Hoch, Josep M. Mercader, Danielle E. Tenen, Melissa Gymrek, Christina R. Hartigan, Michael DeRan, Marcin von Grotthuss, Pierre Fontanillas, Alexandra Spooner, Gaelen Guzman, Amy A. Deik, Kerry A. Pierce, Courtney Dennis, Clary B. Clish, Steven A. Carr, Bridget K. Wagner, Monica Schenone, Maggie C.Y. Ng, Brian H. Chen, Federico Centeno-Cruz, Carlos Zerrweck, Lorena Orozco, David M. Altshuler, Stuart L. Schreiber, Jose C. Florez, Suzanne B.R. Jacobs, Eric S. Lander
      Type 2 diabetes (T2D) affects Latinos at twice the rate seen in populations of European descent. We recently identified a risk haplotype spanning SLC16A11 that explains ∼20% of the increased T2D prevalence in Mexico. Here, through genetic fine-mapping, we define a set of tightly linked variants likely to contain the causal allele(s). We show that variants on the T2D-associated haplotype have two distinct effects: (1) decreasing SLC16A11 expression in liver and (2) disrupting a key interaction with basigin, thereby reducing cell-surface localization. Both independent mechanisms reduce SLC16A11 function and suggest SLC16A11 is the causal gene at this locus. To gain insight into how SLC16A11 disruption impacts T2D risk, we demonstrate that SLC16A11 is a proton-coupled monocarboxylate transporter and that genetic perturbation of SLC16A11 induces changes in fatty acid and lipid metabolism that are associated with increased T2D risk. Our findings suggest that increasing SLC16A11 function could be therapeutically beneficial for T2D. Video
      Graphical abstract image Teaser Genetic variants associated with type 2 diabetes impair function of a monocarboxylate transporter that in turn impacts the metabolic state of the cell.

      PubDate: 2017-07-09T17:13:01Z
       
  • SnapShot: Electrochemical Communication in Biofilms
    • Abstract: Publication date: 29 June 2017
      Source:Cell, Volume 170, Issue 1
      Author(s): Dong-yeon D. Lee, Arthur Prindle, Jintao Liu, Gürol M. Süel
      The role of electricity in biological systems was first appreciated through electrical stimulation experiments performed by Luigi Galvani in the 18th century. These pioneering experiments demonstrated that the behavior of living tissues is governed by the flow of electrochemical species—an insight that gave rise to the modern field of electrophysiology. Since then, electrophysiology has largely remained a bastion of neuroscience. However, exciting recent developments have demonstrated that even simple bacteria residing in communities use electrochemical communication to coordinate population-level behaviors. These recent works are defining the emerging field of bacterial biofilm electrophysiology. To view this SnapShot, open or download the PDF.
      Teaser The role of electricity in biological systems was first appreciated through electrical stimulation experiments performed by Luigi Galvani in the 18th century. These pioneering experiments demonstrated that the behavior of living tissues is governed by the flow of electrochemical species—an insight that gave rise to the modern field of electrophysiology. Since then, electrophysiology has largely remained a bastion of neuroscience. However, exciting recent developments have demonstrated that even simple bacteria residing in communities use electrochemical communication to coordinate population-level behaviors. These recent works are defining the emerging field of bacterial biofilm electrophysiology. To view this SnapShot, open or download the PDF.

      PubDate: 2017-07-09T17:13:01Z
       
  • Development of a Novel Lead that Targets M. tuberculosis Polyketide
           Synthase 13
    • Abstract: Publication date: Available online 29 June 2017
      Source:Cell
      Author(s): Anup Aggarwal, Maloy K. Parai, Nishant Shetty, Deeann Wallis, Lisa Woolhiser, Courtney Hastings, Noton K. Dutta, Stacy Galaviz, Ramesh C. Dhakal, Rupesh Shrestha, Shoko Wakabayashi, Chris Walpole, David Matthews, David Floyd, Paul Scullion, Jennifer Riley, Ola Epemolu, Suzanne Norval, Thomas Snavely, Gregory T. Robertson, Eric J. Rubin, Thomas R. Ioerger, Frik A. Sirgel, Ruben van der Merwe, Paul D. van Helden, Peter Keller, Erik C. Böttger, Petros C. Karakousis, Anne J. Lenaerts, James C. Sacchettini
      Widespread resistance to first-line TB drugs is a major problem that will likely only be resolved through the development of new drugs with novel mechanisms of action. We have used structure-guided methods to develop a lead molecule that targets the thioesterase activity of polyketide synthase Pks13, an essential enzyme that forms mycolic acids, required for the cell wall of Mycobacterium tuberculosis. Our lead, TAM16, is a benzofuran class inhibitor of Pks13 with highly potent in vitro bactericidal activity against drug-susceptible and drug-resistant clinical isolates of M. tuberculosis. In multiple mouse models of TB infection, TAM16 showed in vivo efficacy equal to the first-line TB drug isoniazid, both as a monotherapy and in combination therapy with rifampicin. TAM16 has excellent pharmacological and safety profiles, and the frequency of resistance for TAM16 is ∼100-fold lower than INH, suggesting that it can be developed as a new antitubercular aimed at the acute infection.
      Graphical abstract image Teaser A small molecule inhibitor of M. tuberculosis polyketide synthase shows strong efficacy in murine models of infection.

      PubDate: 2017-07-09T17:13:01Z
       
  • A Sacrifice-for-Survival Mechanism Protects Root Stem Cell Niche from
           Chilling Stress
    • Abstract: Publication date: Available online 22 June 2017
      Source:Cell
      Author(s): Jing Han Hong, Maria Savina, Jing Du, Ajay Devendran, Karthikbabu Kannivadi Ramakanth, Xin Tian, Wei Shi Sim, Victoria V. Mironova, Jian Xu
      Temperature has a profound influence on plant and animal development, but its effects on stem cell behavior and activity remain poorly understood. Here, we characterize the responses of the Arabidopsis root to chilling (low but above-freezing) temperature. Chilling stress at 4°C leads to DNA damage predominantly in root stem cells and their early descendants. However, only newly generated/differentiating columella stem cell daughters (CSCDs) preferentially die in a programmed manner. Inhibition of the DNA damage response in these CSCDs prevents their death but makes the stem cell niche more vulnerable to chilling stress. Mathematical modeling and experimental validation indicate that CSCD death results in the re-establishment of the auxin maximum in the quiescent center (QC) and the maintenance of functional stem cell niche activity under chilling stress. This mechanism improves the root’s ability to withstand the accompanying environmental stresses and to resume growth when optimal temperatures are restored.
      Graphical abstract image Teaser Arabidopsis roots protect their stem cell niche from chilling stress via a selective cell death mechanism regulated by auxin and DNA damage response.

      PubDate: 2017-06-28T08:58:28Z
       
  • Enterochromaffin Cells Are Gut Chemosensors that Couple to Sensory Neural
           Pathways
    • Abstract: Publication date: Available online 22 June 2017
      Source:Cell
      Author(s): Nicholas W. Bellono, James R. Bayrer, Duncan B. Leitch, Joel Castro, Chuchu Zhang, Tracey A. O’Donnell, Stuart M. Brierley, Holly A. Ingraham, David Julius
      Dietary, microbial, and inflammatory factors modulate the gut-brain axis and influence physiological processes ranging from metabolism to cognition. The gut epithelium is a principal site for detecting such agents, but precisely how it communicates with neural elements is poorly understood. Serotonergic enterochromaffin (EC) cells are proposed to fulfill this role by acting as chemosensors, but understanding how these rare and unique cell types transduce chemosensory information to the nervous system has been hampered by their paucity and inaccessibility to single-cell measurements. Here, we circumvent this limitation by exploiting cultured intestinal organoids together with single-cell measurements to elucidate intrinsic biophysical, pharmacological, and genetic properties of EC cells. We show that EC cells express specific chemosensory receptors, are electrically excitable, and modulate serotonin-sensitive primary afferent nerve fibers via synaptic connections, enabling them to detect and transduce environmental, metabolic, and homeostatic information from the gut directly to the nervous system.
      Graphical abstract image Teaser Organoid cultures are exploited to characterize rare chemosensory cells in the gut, revealing their receptive and signaling properties and demonstrating direct communication with neural sensory pathways.

      PubDate: 2017-06-28T08:58:28Z
       
  • Friction Mediates Scission of Tubular Membranes Scaffolded by BAR Proteins
    • Abstract: Publication date: Available online 22 June 2017
      Source:Cell
      Author(s): Mijo Simunovic, Jean-Baptiste Manneville, Henri-François Renard, Emma Evergren, Krishnan Raghunathan, Dhiraj Bhatia, Anne K. Kenworthy, Gregory A. Voth, Jacques Prost, Harvey T. McMahon, Ludger Johannes, Patricia Bassereau, Andrew Callan-Jones
      Membrane scission is essential for intracellular trafficking. While BAR domain proteins such as endophilin have been reported in dynamin-independent scission of tubular membrane necks, the cutting mechanism has yet to be deciphered. Here, we combine a theoretical model, in vitro, and in vivo experiments revealing how protein scaffolds may cut tubular membranes. We demonstrate that the protein scaffold bound to the underlying tube creates a frictional barrier for lipid diffusion; tube elongation thus builds local membrane tension until the membrane undergoes scission through lysis. We call this mechanism friction-driven scission (FDS). In cells, motors pull tubes, particularly during endocytosis. Through reconstitution, we show that motors not only can pull out and extend protein-scaffolded tubes but also can cut them by FDS. FDS is generic, operating even in the absence of amphipathic helices in the BAR domain, and could in principle apply to any high-friction protein and membrane assembly.
      Graphical abstract image Teaser Proteins create points of friction at sites of membrane tubulation leading to scission and vesicle budding.

      PubDate: 2017-06-28T08:58:28Z
       
  • De Novo Epigenetic Programs Inhibit PD-1 Blockade-Mediated T Cell
           Rejuvenation
    • Abstract: Publication date: Available online 22 June 2017
      Source:Cell
      Author(s): Hazem E. Ghoneim, Yiping Fan, Ardiana Moustaki, Hossam A. Abdelsamed, Pradyot Dash, Pranay Dogra, Robert Carter, Walid Awad, Geoff Neale, Paul G. Thomas, Ben Youngblood
      Immune-checkpoint-blockade (ICB)-mediated rejuvenation of exhausted T cells has emerged as a promising approach for treating various cancers and chronic infections. However, T cells that become fully exhausted during prolonged antigen exposure remain refractory to ICB-mediated rejuvenation. We report that blocking de novo DNA methylation in activated CD8 T cells allows them to retain their effector functions despite chronic stimulation during a persistent viral infection. Whole-genome bisulfite sequencing of antigen-specific murine CD8 T cells at the effector and exhaustion stages of an immune response identified progressively acquired heritable de novo methylation programs that restrict T cell expansion and clonal diversity during PD-1 blockade treatment. Moreover, these exhaustion-associated DNA-methylation programs were acquired in tumor-infiltrating PD-1hi CD8 T cells, and approaches to reverse these programs improved T cell responses and tumor control during ICB. These data establish de novo DNA-methylation programming as a regulator of T cell exhaustion and barrier of ICB-mediated T cell rejuvenation.
      Graphical abstract image Teaser De novo DNA methylation programs promote T cell exhaustion, and inhibiting these programs can enhance immune-checkpoint-blockade-mediated T cell rejuventation and ultimately facilitate the control of chronic viral infections and tumor growth.

      PubDate: 2017-06-28T08:58:28Z
       
  • Sorting Out Complex Thoughts and Messy Emotions
    • Abstract: Publication date: 15 June 2017
      Source:Cell, Volume 169, Issue 7
      Author(s): Stephen Matheson


      PubDate: 2017-06-21T02:59:48Z
       
  • The Measure of a Man
    • Abstract: Publication date: 15 June 2017
      Source:Cell, Volume 169, Issue 7
      Author(s): Neil Savage
      Moving beyond simple fitness tracking, wearable devices may soon offer opportunities for monitoring health and bring vast amounts of new data to the study of human diseases.
      Teaser Moving beyond simple fitness tracking, wearable devices may soon offer opportunities for monitoring health and bring vast amounts of new data to the study of human diseases.

      PubDate: 2017-06-21T02:59:48Z
       
  • Getting Surprising Answers to Unasked Questions
    • Abstract: Publication date: 15 June 2017
      Source:Cell, Volume 169, Issue 7
      Author(s): Ueli Schibler


      PubDate: 2017-06-21T02:59:48Z
       
  • Microbiome and Longevity: Gut Microbes Send Signals to Host Mitochondria
    • Abstract: Publication date: 15 June 2017
      Source:Cell, Volume 169, Issue 7
      Author(s): Jan Gruber, Brian K. Kennedy
      The microbiome has emerged as a major determinant of the functioning of host organisms, affecting both health and disease. Here, Han et al. use the workhorse of aging research, C. elegans, to identify specific mechanisms by which gut bacteria influence mitochondrial dynamics and aging, a first step toward analogous manipulations to modulate human aging.
      Teaser The microbiome has emerged as a major determinant of the functioning of host organisms, affecting both health and disease. Here, Han et al. use the workhorse of aging research, C. elegans, to identify specific mechanisms by which gut bacteria influence mitochondrial dynamics and aging, a first step toward analogous manipulations to modulate human aging.

      PubDate: 2017-06-21T02:59:48Z
       
  • Just a Spoonful of Sugar Helps the Tolerance Go Up
    • Abstract: Publication date: 15 June 2017
      Source:Cell, Volume 169, Issue 7
      Author(s): Alexander V. Chervonsky
      Survival of deleterious infections depends significantly on how much stress the affected organism can tolerate. In this issue, Weis et al. find that mice can survive sepsis by maintaining normoglycemia through ferritin’s capacity to inactivate Fe2+ ions that otherwise induce free radicals impacting gluconeogenesis in the liver.
      Teaser Survival of deleterious infections depends significantly on how much stress the affected organism can tolerate. In this issue, Weis et al. find that mice can survive sepsis by maintaining normoglycemia through ferritin’s capacity to inactivate Fe2+ ions that otherwise induce free radicals impacting gluconeogenesis in the liver.

      PubDate: 2017-06-21T02:59:48Z
       
  • DAMed in (Trem) 2 Steps
    • Abstract: Publication date: 15 June 2017
      Source:Cell, Volume 169, Issue 7
      Author(s): Sandro Da Mesquita, Jonathan Kipnis
      The role of microglia in neurodegenerative diseases has been controversial. In this issue, Keren-Shaul et al. identify a unique population of disease-associated microglia (DAM) that develop in two steps and may help to restrict damage in Alzheimer and related diseases.
      Teaser The role of microglia in neurodegenerative diseases has been controversial. In this issue, Keren-Shaul et al. identify a unique population of disease-associated microglia (DAM) that develop in two steps and may help to restrict damage in Alzheimer and related diseases.

      PubDate: 2017-06-21T02:59:48Z
       
  • Sex at Atomic Resolution
    • Abstract: Publication date: 15 June 2017
      Source:Cell, Volume 169, Issue 7
      Author(s): Jae Yeon Hwang, Jean-Ju Chung
      Interspecies fertilization is rare, partly due to species separation enforced at the molecular level. In this issue, Raj et al. now reveal the crystal structures of mollusk egg coat protein, VERL, complexed with cognate sperm protein lysin. Given that VERL is structurally similar to mammalian ZP2, the mechanism elucidating species-specific gamete recognition likely exists in mammals.
      Teaser Interspecies fertilization is rare, partly due to species separation enforced at the molecular level. In this issue, Raj et al. now reveal the crystal structures of mollusk egg coat protein, VERL, complexed with cognate sperm protein lysin. Given that VERL is structurally similar to mammalian ZP2, the mechanism elucidating species-specific gamete recognition likely exists in mammals.

      PubDate: 2017-06-21T02:59:48Z
       
  • An Expanded View of Complex Traits: From Polygenic to Omnigenic
    • Abstract: Publication date: 15 June 2017
      Source:Cell, Volume 169, Issue 7
      Author(s): Evan A. Boyle, Yang I. Li, Jonathan K. Pritchard
      A central goal of genetics is to understand the links between genetic variation and disease. Intuitively, one might expect disease-causing variants to cluster into key pathways that drive disease etiology. But for complex traits, association signals tend to be spread across most of the genome—including near many genes without an obvious connection to disease. We propose that gene regulatory networks are sufficiently interconnected such that all genes expressed in disease-relevant cells are liable to affect the functions of core disease-related genes and that most heritability can be explained by effects on genes outside core pathways. We refer to this hypothesis as an “omnigenic” model.
      Teaser Many complex genetic traits arise from large numbers of variants, each with small effects. This Perspective argues that risk is ultimately driven by an even larger number of genes with no direct impact on the phenotype or disease whose effects are propagated through regulatory networks.

      PubDate: 2017-06-21T02:59:48Z
       
  • Dynamic RNA Modifications in Gene Expression Regulation
    • Abstract: Publication date: 15 June 2017
      Source:Cell, Volume 169, Issue 7
      Author(s): Ian A. Roundtree, Molly E. Evans, Tao Pan, Chuan He
      Over 100 types of chemical modifications have been identified in cellular RNAs. While the 5′ cap modification and the poly(A) tail of eukaryotic mRNA play key roles in regulation, internal modifications are gaining attention for their roles in mRNA metabolism. The most abundant internal mRNA modification is N 6-methyladenosine (m6A), and identification of proteins that install, recognize, and remove this and other marks have revealed roles for mRNA modification in nearly every aspect of the mRNA life cycle, as well as in various cellular, developmental, and disease processes. Abundant noncoding RNAs such as tRNAs, rRNAs, and spliceosomal RNAs are also heavily modified and depend on the modifications for their biogenesis and function. Our understanding of the biological contributions of these different chemical modifications is beginning to take shape, but it’s clear that in both coding and noncoding RNAs, dynamic modifications represent a new layer of control of genetic information.
      Teaser Post-transcriptional modification of mRNAs and noncoding RNAs introduces a layer of control over stability and function that shapes the functional proteome.

      PubDate: 2017-06-21T02:59:48Z
       
  • Independent and Stochastic Action of DNA Polymerases in the Replisome
    • Abstract: Publication date: 15 June 2017
      Source:Cell, Volume 169, Issue 7
      Author(s): James E. Graham, Kenneth J. Marians, Stephen C. Kowalczykowski
      It has been assumed that DNA synthesis by the leading- and lagging-strand polymerases in the replisome must be coordinated to avoid the formation of significant gaps in the nascent strands. Using real-time single-molecule analysis, we establish that leading- and lagging-strand DNA polymerases function independently within a single replisome. Although average rates of DNA synthesis on leading and lagging strands are similar, individual trajectories of both DNA polymerases display stochastically switchable rates of synthesis interspersed with distinct pauses. DNA unwinding by the replicative helicase may continue during such pauses, but a self-governing mechanism, where helicase speed is reduced by ∼80%, permits recoupling of polymerase to helicase. These features imply a more dynamic, kinetically discontinuous replication process, wherein contacts within the replisome are continually broken and reformed. We conclude that the stochastic behavior of replisome components ensures complete DNA duplication without requiring coordination of leading- and lagging-strand synthesis. PaperClip
      Graphical abstract image Teaser Polymerases within the replisome operate independently and discontinuously, and they are not coordinated.

      PubDate: 2017-06-21T02:59:48Z
       
  • SAF-A Regulates Interphase Chromosome Structure through Oligomerization
           with Chromatin-Associated RNAs
    • Abstract: Publication date: 15 June 2017
      Source:Cell, Volume 169, Issue 7
      Author(s): Ryu-Suke Nozawa, Lora Boteva, Dinesh C. Soares, Catherine Naughton, Alison R. Dun, Adam Buckle, Bernard Ramsahoye, Peter C. Bruton, Rebecca S. Saleeb, Maria Arnedo, Bill Hill, Rory R. Duncan, Sutherland K. Maciver, Nick Gilbert
      Higher eukaryotic chromosomes are organized into topologically constrained functional domains; however, the molecular mechanisms required to sustain these complex interphase chromatin structures are unknown. A stable matrix underpinning nuclear organization was hypothesized, but the idea was abandoned as more dynamic models of chromatin behavior became prevalent. Here, we report that scaffold attachment factor A (SAF-A), originally identified as a structural nuclear protein, interacts with chromatin-associated RNAs (caRNAs) via its RGG domain to regulate human interphase chromatin structures in a transcription-dependent manner. Mechanistically, this is dependent on SAF-A’s AAA+ ATPase domain, which mediates cycles of protein oligomerization with caRNAs, in response to ATP binding and hydrolysis. SAF-A oligomerization decompacts large-scale chromatin structure while SAF-A loss or monomerization promotes aberrant chromosome folding and accumulation of genome damage. Our results show that SAF-A and caRNAs form a dynamic, transcriptionally responsive chromatin mesh that organizes large-scale chromosome structures and protects the genome from instability.
      Graphical abstract image Teaser A scaffolding protein interacts with chromatin-associated RNAs to regulate human interphase chromatin structures in a transcription-dependent manner.

      PubDate: 2017-06-21T02:59:48Z
       
  • Antibacterial Nucleoside-Analog Inhibitor of Bacterial RNA Polymerase
    • Abstract: Publication date: 15 June 2017
      Source:Cell, Volume 169, Issue 7
      Author(s): Sonia I. Maffioli, Yu Zhang, David Degen, Thomas Carzaniga, Giancarlo Del Gatto, Stefania Serina, Paolo Monciardini, Carlo Mazzetti, Paola Guglierame, Gianpaolo Candiani, Alina Iulia Chiriac, Giuseppe Facchetti, Petra Kaltofen, Hans-Georg Sahl, Gianni Dehò, Stefano Donadio, Richard H. Ebright
      Drug-resistant bacterial pathogens pose an urgent public-health crisis. Here, we report the discovery, from microbial-extract screening, of a nucleoside-analog inhibitor that inhibits bacterial RNA polymerase (RNAP) and exhibits antibacterial activity against drug-resistant bacterial pathogens: pseudouridimycin (PUM). PUM is a natural product comprising a formamidinylated, N-hydroxylated Gly-Gln dipeptide conjugated to 6′-amino-pseudouridine. PUM potently and selectively inhibits bacterial RNAP in vitro, inhibits bacterial growth in culture, and clears infection in a mouse model of Streptococcus pyogenes peritonitis. PUM inhibits RNAP through a binding site on RNAP (the NTP addition site) and mechanism (competition with UTP for occupancy of the NTP addition site) that differ from those of the RNAP inhibitor and current antibacterial drug rifampin (Rif). PUM exhibits additive antibacterial activity when co-administered with Rif, exhibits no cross-resistance with Rif, and exhibits a spontaneous resistance rate an order-of-magnitude lower than that of Rif. PUM is a highly promising lead for antibacterial therapy.
      Graphical abstract image Teaser Pseudouridimycin competes with incoming nucleotides to inhibit bacterial RNA polymerase, effectively blocking growth of a broad range of pathogens.

      PubDate: 2017-06-21T02:59:48Z
       
  • Microbial Genetic Composition Tunes Host Longevity
    • Abstract: Publication date: 15 June 2017
      Source:Cell, Volume 169, Issue 7
      Author(s): Bing Han, Priya Sivaramakrishnan, Chih-Chun J. Lin, Isaiah A.A. Neve, Jingquan He, Li Wei Rachel Tay, Jessica N. Sowa, Antons Sizovs, Guangwei Du, Jin Wang, Christophe Herman, Meng C. Wang
      Homeostasis of the gut microbiota critically influences host health and aging. Developing genetically engineered probiotics holds great promise as a new therapeutic paradigm to promote healthy aging. Here, through screening 3,983 Escherichia coli mutants, we discovered that 29 bacterial genes, when deleted, increase longevity in the host Caenorhabditis elegans. A dozen of these bacterial mutants also protect the host from age-related progression of tumor growth and amyloid-beta accumulation. Mechanistically, we discovered that five bacterial mutants promote longevity through increased secretion of the polysaccharide colanic acid (CA), which regulates mitochondrial dynamics and unfolded protein response (UPRmt) in the host. Purified CA polymers are sufficient to promote longevity via ATFS-1, the host UPRmt-responsive transcription factor. Furthermore, the mitochondrial changes and longevity effects induced by CA are conserved across different species. Together, our results identified molecular targets for developing pro-longevity microbes and a bacterial metabolite acting on host mitochondria to promote longevity.
      Graphical abstract image Teaser The genetic composition of gut microbes controls the production of metabolites that impact host longevity.

      PubDate: 2017-06-21T02:59:48Z
       
  • Metabolic Adaptation Establishes Disease Tolerance to Sepsis
    • Abstract: Publication date: 15 June 2017
      Source:Cell, Volume 169, Issue 7
      Author(s): Sebastian Weis, Ana Rita Carlos, Maria Raquel Moita, Sumnima Singh, Birte Blankenhaus, Silvia Cardoso, Rasmus Larsen, Sofia Rebelo, Sascha Schäuble, Laura Del Barrio, Gilles Mithieux, Fabienne Rajas, Sandro Lindig, Michael Bauer, Miguel P. Soares
      Sepsis is an often lethal syndrome resulting from maladaptive immune and metabolic responses to infection, compromising host homeostasis. Disease tolerance is a defense strategy against infection that preserves host homeostasis without exerting a direct negative impact on pathogens. Here, we demonstrate that induction of the iron-sequestering ferritin H chain (FTH) in response to polymicrobial infections is critical to establish disease tolerance to sepsis. The protective effect of FTH is exerted via a mechanism that counters iron-driven oxidative inhibition of the liver glucose-6-phosphatase (G6Pase), and in doing so, sustains endogenous glucose production via liver gluconeogenesis. This is required to prevent the development of hypoglycemia that otherwise compromises disease tolerance to sepsis. FTH overexpression or ferritin administration establish disease tolerance therapeutically. In conclusion, disease tolerance to sepsis relies on a crosstalk between adaptive responses controlling iron and glucose metabolism, required to maintain blood glucose within a physiologic range compatible with host survival.
      Graphical abstract image Teaser Disease tolerance to sepsis depends on a crosstalk between iron and glucose- metabolic responses that maintain blood glucose levels within a dynamic range compatible with host survival.

      PubDate: 2017-06-21T02:59:48Z
       
  • Structural Basis of Egg Coat-Sperm Recognition at Fertilization
    • Abstract: Publication date: 15 June 2017
      Source:Cell, Volume 169, Issue 7
      Author(s): Isha Raj, Hamed Sadat Al Hosseini, Elisa Dioguardi, Kaoru Nishimura, Ling Han, Alessandra Villa, Daniele de Sanctis, Luca Jovine
      Recognition between sperm and the egg surface marks the beginning of life in all sexually reproducing organisms. This fundamental biological event depends on the species-specific interaction between rapidly evolving counterpart molecules on the gametes. We report biochemical, crystallographic, and mutational studies of domain repeats 1–3 of invertebrate egg coat protein VERL and their interaction with cognate sperm protein lysin. VERL repeats fold like the functionally essential N-terminal repeat of mammalian sperm receptor ZP2, whose structure is also described here. Whereas sequence-divergent repeat 1 does not bind lysin, repeat 3 binds it non-species specifically via a high-affinity, largely hydrophobic interface. Due to its intermediate binding affinity, repeat 2 selectively interacts with lysin from the same species. Exposure of a highly positively charged surface of VERL-bound lysin suggests that complex formation both disrupts the organization of egg coat filaments and triggers their electrostatic repulsion, thereby opening a hole for sperm penetration and fusion.
      Graphical abstract image Teaser Molecular insights into egg-sperm recognition point to the basis of species-specific fertilization.

      PubDate: 2017-06-21T02:59:48Z
       
  • Comprehensive and Integrative Genomic Characterization of Hepatocellular
           Carcinoma
    • Abstract: Publication date: 15 June 2017
      Source:Cell, Volume 169, Issue 7
      Author(s): The Cancer Genome Atlas Research NetworkAdrianAllyMirunaBalasundaramRebeccaCarlsenEricChuahAmandaClarkeNoreenDhallaRobert A.HoltSteven J.M.JonesDarleneLeeYussanneMaMarco A.MarraMichaelMayoRichard A.MooreAndrew J.MungallJacqueline E.ScheinPayalSipahimalaniAngelaTamNinaThiessenDorothyCheungTinaWongDeniseBrooksA. GordonRobertsonReanneBowlbyKarenMungallSaraSadeghiLiuXiKyleCovingtonEveShinbrotDavid A.WheelerRichard A.GibbsLawrence A.DonehowerLinghuaWangJayBowenJulie M.Gastier-FosterMarkGerkenCarmenHelselKristen M.LeraasTara M.LichtenbergNilsa C.RamirezLisaWiseErikZmudaStacey B.GabrielMatthewMeyersonCarrieCibulskisBradley A.MurrayJuliannShihRameenBeroukhimAndrew D.CherniackSteven E.SchumacherGordonSaksenaChandra SekharPedamalluLyndaChinGadGetzMichaelNobleHaileiZhangDavidHeimanJuokChoNilsGehlenborgGordonSaksenaDouglasVoetPeiLinScottFrazerTimothyDefreitasSamMeierMichaelLawrenceJaegilKimChad J.CreightonDonnaMuznyHarshaVardhanDoddapaneniJianhongHuMinWangDonnaMortonViktoriyaKorchinaYiHanHuyenDinhLoraLewisMichelleBellairXiupingLiuJirehSantibanezRobertGlennSandraLeeWalkerHaleJoel S.ParkerMatthew D.WilkersonD. NeilHayesSheila M.ReynoldsIlyaShmulevichWeiZhangYuexinLiuLisaIypeHalaMakhloufMichael S.TorbensonSanjayKakarMatthew M.YehDhanpatJainDavid E.KleinerDhanpatJainRenumathyDhanasekaranHashem B.El-SeragSun YoungYimJohn N.WeinsteinLopaMishraJianpingZhangRehanAkbaniShiyunLingZhenlinJuXiaopingSuApurva M.HegdeGordon B.MillsYilingLuJianChenJu-SeogLeeBo HwaSohnJae JunShimPanTongHiroyukiAburataniShogoYamamotoKenjiTatsunoWeiLiZhengXiaNicolasStranskyEricSeiserFedericoInnocentiJianjiongGaoRitikaKundraHongxinZhangZacharyHeinsAngelicaOchoaChrisSanderMarcLadanyiRonglaiShenArshiAroraFranciscoSanchez-VegaNikolausSchultzKatayoonKasaianAmieRadenbaughKarl-DimiterBissigDavid D.MooreYasushiTotokiHiromiNakamuraTatsuhiroShibataChristinaYauKileyGraimJoshStuartDavidHausslerBetty L.SlagleAkinyemi I.OjesinaPanagiotisKatsonisAmandaKoireOlivierLichtargeTeng-KueiHsuMartin L.FergusonJohn A.DemchokInaFelauMargiShethRoyTarnuzzerZhiningWangLimingYangJean C.ZenklusenJiashanZhangCarolyn M.HutterHeidi J.SofiaRoel G.W.VerhaakSiyuanZhengFrederickLangSudhaChudamaniJiaLiuLaxmiLollaYeWuRashiNareshToddPihlCharlieSunYunhuWanChristopherBenzAmy H.PerouLeigh B.ThorneLoriBoiceMeiHuangW. KimrynRathmellHoutanNoushmehrFabiano PintoSaggioroDaniela Pretti da CunhaTirapelliCarlos Gilberto CarlottiJuniorEnio DavidMenteOrlando de CastroSilvaJr.Felipe AmstaldenTrevisanKoo JeongKangKeun SooAhnNasra H.GiamaCatherine D.MoserThomas J.GiordanoMichelleVincoTheodore H.WellingDanielCrainErinCurleyJohannaGardnerDavidMalleryScottMorrisJosephPaulauskisRobertPennyCandaceSheltonTroySheltonRobinKelleyJoong-WonParkVishal S.ChandanLewis R.RobertsOliver F.BatheCurt H.HagedornJ. ToddAumanDaniel R.O'BrienJean-Pierre A.KocherCorbin D.JonesPiotr A.MieczkowskiCharles M.PerouTaraSkellyDonghuiTanUmadeviVeluvoluSaianandBaluTomBodenheimerAlan P.HoyleStuart R.JefferysShaowuMengLisle E.MoseYanShiJanae V.SimonsMatthew G.SolowayJeffreyRoachKatherine A.HoadleyStephen B.BaylinHuiShenToshinoriHinoueMoiz S.BootwallaDavid J.Van Den BergDaniel J.WeisenbergerPhillip H.LaiAndreaHolbrookMarioBerriosPeter W.Laird
      Liver cancer has the second highest worldwide cancer mortality rate and has limited therapeutic options. We analyzed 363 hepatocellular carcinoma (HCC) cases by whole-exome sequencing and DNA copy number analyses, and we analyzed 196 HCC cases by DNA methylation, RNA, miRNA, and proteomic expression also. DNA sequencing and mutation analysis identified significantly mutated genes, including LZTR1, EEF1A1, SF3B1, and SMARCA4. Significant alterations by mutation or downregulation by hypermethylation in genes likely to result in HCC metabolic reprogramming (ALB, APOB, and CPS1) were observed. Integrative molecular HCC subtyping incorporating unsupervised clustering of five data platforms identified three subtypes, one of which was associated with poorer prognosis in three HCC cohorts. Integrated analyses enabled development of a p53 target gene expression signature correlating with poor survival. Potential therapeutic targets for which inhibitors exist include WNT signaling, MDM4, MET, VEGFA, MCL1, IDH1, TERT, and immune checkpoint proteins CTLA-4, PD-1, and PD-L1.
      Graphical abstract image Teaser Multiplex molecular profiling of human hepatocellular carcinoma patients provides insight into subtype characteristics and points toward key pathways to target therapeutically.

      PubDate: 2017-06-21T02:59:48Z
       
  • Landscape of Infiltrating T Cells in Liver Cancer Revealed by Single-Cell
           Sequencing
    • Abstract: Publication date: 15 June 2017
      Source:Cell, Volume 169, Issue 7
      Author(s): Chunhong Zheng, Liangtao Zheng, Jae-Kwang Yoo, Huahu Guo, Yuanyuan Zhang, Xinyi Guo, Boxi Kang, Ruozhen Hu, Julie Y. Huang, Qiming Zhang, Zhouzerui Liu, Minghui Dong, Xueda Hu, Wenjun Ouyang, Jirun Peng, Zemin Zhang
      Systematic interrogation of tumor-infiltrating lymphocytes is key to the development of immunotherapies and the prediction of their clinical responses in cancers. Here, we perform deep single-cell RNA sequencing on 5,063 single T cells isolated from peripheral blood, tumor, and adjacent normal tissues from six hepatocellular carcinoma patients. The transcriptional profiles of these individual cells, coupled with assembled T cell receptor (TCR) sequences, enable us to identify 11 T cell subsets based on their molecular and functional properties and delineate their developmental trajectory. Specific subsets such as exhausted CD8+ T cells and Tregs are preferentially enriched and potentially clonally expanded in hepatocellular carcinoma (HCC), and we identified signature genes for each subset. One of the genes, layilin, is upregulated on activated CD8+ T cells and Tregs and represses the CD8+ T cell functions in vitro. This compendium of transcriptome data provides valuable insights and a rich resource for understanding the immune landscape in cancers.
      Graphical abstract image Teaser Analysis of T cell populations from hepatocellular carcinoma patients using single-cell sequencing reveals distinct subtypes and clonal expansion of infiltrating lymphocytes.

      PubDate: 2017-06-21T02:59:48Z
       
  • A Mechanogenetic Toolkit for Interrogating Cell Signaling in Space and
           Time
    • Abstract: Publication date: 15 June 2017
      Source:Cell, Volume 169, Issue 7
      Author(s): Daeha Seo, Kaden M. Southard, Ji-wook Kim, Hyun Jung Lee, Justin Farlow, Jung-uk Lee, David B. Litt, Thomas Haas, A. Paul Alivisatos, Jinwoo Cheon, Zev J. Gartner, Young-wook Jun


      PubDate: 2017-06-21T02:59:48Z
       
  • SnapShot: Phosphoregulation of Mitosis
    • Abstract: Publication date: 15 June 2017
      Source:Cell, Volume 169, Issue 7
      Author(s): Andrew Burgess, Jenny Vuong, Samuel Rogers, Marcos Malumbres, Seán I. O’Donoghue
      During mitosis, a cell divides its duplicated genome into two identical daughter cells. This process must occur without errors to prevent proliferative diseases (e.g., cancer). A key mechanism controlling mitosis is the precise timing of more than 32,000 phosphorylation and dephosphorylation events by a network of kinases and counterbalancing phosphatases. The identity, magnitude, and temporal regulation of these events have emerged recently, largely from advances in mass spectrometry. Here, we show phosphoevents currently believed to be key regulators of mitosis. For an animated version of this SnapShot, please see http://www.cell.com/cell/enhanced/odonoghue2.
      Teaser During mitosis, a cell divides its duplicated genome into two identical daughter cells. This process must occur without errors to prevent proliferative diseases (e.g., cancer). A key mechanism controlling mitosis is the precise timing of more than 32,000 phosphorylation and dephosphorylation events by a network of kinases and counterbalancing phosphatases. The identity, magnitude, and temporal regulation of these events have emerged recently, largely from advances in mass spectrometry. Here, we show phosphoevents currently believed to be key regulators of mitosis. For an animated version of this SnapShot, please see http://www.cell.com/cell/enhanced/odonoghue2.

      PubDate: 2017-06-21T02:59:48Z
       
  • Visuomotor Coupling Shapes the Functional Development of Mouse Visual
           Cortex
    • Abstract: Publication date: Available online 9 June 2017
      Source:Cell
      Author(s): Alexander Attinger, Bo Wang, Georg B. Keller
      The emergence of sensory-guided behavior depends on sensorimotor coupling during development. How sensorimotor experience shapes neural processing is unclear. Here, we show that the coupling between motor output and visual feedback is necessary for the functional development of visual processing in layer 2/3 (L2/3) of primary visual cortex (V1) of the mouse. Using a virtual reality system, we reared mice in conditions of normal or random visuomotor coupling. We recorded the activity of identified excitatory and inhibitory L2/3 neurons in response to transient visuomotor mismatches in both groups of mice. Mismatch responses in excitatory neurons were strongly experience dependent and driven by a transient release from inhibition mediated by somatostatin-positive interneurons. These data are consistent with a model in which L2/3 of V1 computes a difference between an inhibitory visual input and an excitatory locomotion-related input, where the balance between these two inputs is finely tuned by visuomotor experience.
      Graphical abstract image Teaser The coupling of sensory and motor experience during development shapes visual perception by tuning a cortical circuit that compares inhibitory visual input and excitatory motor input and is able to detect mismatches between actual and expected sensory experience.

      PubDate: 2017-06-10T15:18:01Z
       
  • A Unique Microglia Type Associated with Restricting Development of
           Alzheimer’s Disease
    • Abstract: Publication date: Available online 8 June 2017
      Source:Cell
      Author(s): Hadas Keren-Shaul, Amit Spinrad, Assaf Weiner, Orit Matcovitch-Natan, Raz Dvir-Szternfeld, Tyler K. Ulland, Eyal David, Kuti Baruch, David Lara-Astaiso, Beata Toth, Shalev Itzkovitz, Marco Colonna, Michal Schwartz, Ido Amit
      Alzheimer’s disease (AD) is a detrimental neurodegenerative disease with no effective treatments. Due to cellular heterogeneity, defining the roles of immune cell subsets in AD onset and progression has been challenging. Using transcriptional single-cell sorting, we comprehensively map all immune populations in wild-type and AD-transgenic (Tg-AD) mouse brains. We describe a novel microglia type associated with neurodegenerative diseases (DAM) and identify markers, spatial localization, and pathways associated with these cells. Immunohistochemical staining of mice and human brain slices shows DAM with intracellular/phagocytic Aβ particles. Single-cell analysis of DAM in Tg-AD and triggering receptor expressed on myeloid cells 2 (Trem2)−/− Tg-AD reveals that the DAM program is activated in a two-step process. Activation is initiated in a Trem2-independent manner that involves downregulation of microglia checkpoints, followed by activation of a Trem2-dependent program. This unique microglia-type has the potential to restrict neurodegeneration, which may have important implications for future treatment of AD and other neurodegenerative diseases. Video
      Graphical abstract image Teaser A new type of microglia associated with restricting neurodegeneration may have important implications for treatment of Alzheimer’s and related diseases.

      PubDate: 2017-06-10T15:18:01Z
       
  • Structure of the Human Lipid Exporter ABCA1
    • Abstract: Publication date: Available online 8 June 2017
      Source:Cell
      Author(s): Hongwu Qian, Xin Zhao, Pingping Cao, Jianlin Lei, Nieng Yan, Xin Gong
      ABCA1, an ATP-binding cassette (ABC) subfamily A exporter, mediates the cellular efflux of phospholipids and cholesterol to the extracellular acceptor apolipoprotein A-I (apoA-I) for generation of nascent high-density lipoprotein (HDL). Mutations of human ABCA1 are associated with Tangier disease and familial HDL deficiency. Here, we report the cryo-EM structure of human ABCA1 with nominal resolutions of 4.1 Å for the overall structure and 3.9 Å for the massive extracellular domain. The nucleotide-binding domains (NBDs) display a nucleotide-free state, while the two transmembrane domains (TMDs) contact each other through a narrow interface in the intracellular leaflet of the membrane. In addition to TMDs and NBDs, two extracellular domains of ABCA1 enclose an elongated hydrophobic tunnel. Structural mapping of dozens of disease-related mutations allows potential interpretation of their diverse pathogenic mechanisms. Structural-based analysis suggests a plausible “lateral access” mechanism for ABCA1-mediated lipid export that may be distinct from the conventional alternating-access paradigm.
      Graphical abstract image Teaser The human ABCA1 transporter moves lipids from within the membrane through a narrow gate to support HDL biosynthesis.

      PubDate: 2017-06-10T15:18:01Z
       
  • Cryo-EM Reveals How Human Cytoplasmic Dynein Is Auto-inhibited and
           Activated
    • Abstract: Publication date: Available online 8 June 2017
      Source:Cell
      Author(s): Kai Zhang, Helen E. Foster, Arnaud Rondelet, Samuel E. Lacey, Nadia Bahi-Buisson, Alexander W. Bird, Andrew P. Carter
      Cytoplasmic dynein-1 binds dynactin and cargo adaptor proteins to form a transport machine capable of long-distance processive movement along microtubules. However, it is unclear why dynein-1 moves poorly on its own or how it is activated by dynactin. Here, we present a cryoelectron microscopy structure of the complete 1.4-megadalton human dynein-1 complex in an inhibited state known as the phi-particle. We reveal the 3D structure of the cargo binding dynein tail and show how self-dimerization of the motor domains locks them in a conformation with low microtubule affinity. Disrupting motor dimerization with structure-based mutagenesis drives dynein-1 into an open form with higher affinity for both microtubules and dynactin. We find the open form is also inhibited for movement and that dynactin relieves this by reorienting the motor domains to interact correctly with microtubules. Our model explains how dynactin binding to the dynein-1 tail directly stimulates its motor activity.
      Graphical abstract image Teaser Cryo-EM of human cytoplasmic dynein-1 reveals the mechanism underlying its auto-inhibition and activation.

      PubDate: 2017-06-10T15:18:01Z
       
  • Beyond Statins: New Therapeutic Frontiers for Cardiovascular Disease
    • Abstract: Publication date: 1 June 2017
      Source:Cell, Volume 169, Issue 6
      Author(s): Sri Devi Narasimhan


      PubDate: 2017-06-06T13:04:20Z
       
  • How Do We Recognize a Face?
    • Abstract: Publication date: 1 June 2017
      Source:Cell, Volume 169, Issue 6
      Author(s): Rodrigo Quian Quiroga
      How individual faces are encoded by neurons in high-level visual areas has been a subject of active debate. An influential model is that neurons encode specific faces. However, Chang and Tsao conclusively show that, instead, these neurons encode features along specific axes, which explains why they were previously found to respond to apparently different faces.
      Teaser How individual faces are encoded by neurons in high-level visual areas has been a subject of active debate. An influential model is that neurons encode specific faces. However, Chang and Tsao conclusively show that, instead, these neurons encode features along specific axes, which explains why they were previously found to respond to apparently different faces.

      PubDate: 2017-06-06T13:04:20Z
       
 
 
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