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Journal Cover Cell
  [SJR: 28.188]   [H-I: 616]   [773 followers]  Follow
    
   Full-text available via subscription Subscription journal
   ISSN (Print) 0092-8674 - ISSN (Online) 1097-4172
   Published by Elsevier Homepage  [3033 journals]
  • 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
       
  • Noninvasive Neuromodulation Goes Deep
    • Abstract: Publication date: 1 June 2017
      Source:Cell, Volume 169, Issue 6
      Author(s): Jacek Dmochowski, Marom Bikson
      Modulating deep regions of the brain with noninvasive technology has challenged researchers for decades. In a new study, Grossman et al. leverage the emergence of a slowly oscillating “beat” from intersecting high-frequency electric fields to stimulate deep brain regions, opening a frontier in the biophysics and technology of brain stimulation.
      Teaser Modulating deep regions of the brain with noninvasive technology has challenged researchers for decades. In a new study, Grossman et al. leverage the emergence of a slowly oscillating “beat” from intersecting high-frequency electric fields to stimulate deep brain regions, opening a frontier in the biophysics and technology of brain stimulation.

      PubDate: 2017-06-06T13:04:20Z
       
  • Aldehydes Pose a Threat to BRCA2 Mutation Carriers
    • Abstract: Publication date: 1 June 2017
      Source:Cell, Volume 169, Issue 6
      Author(s): Kalindi Parmar, Alan D. D’Andrea
      Humans with inherited heterozygous BRCA2 mutations have an increased risk of developing cancer; however, what triggers carcinogenesis in these individuals is unclear. Tan et al. find that environmental and metabolic aldehydes pose a threat to these individuals by promoting degradation of wild-type BRCA2 protein, thereby predisposing them to genomic instability and perhaps to cancer.
      Teaser Humans with inherited heterozygous BRCA2 mutations have an increased risk of developing cancer; however, what triggers carcinogenesis in these individuals is unclear. Tan et al. find that environmental and metabolic aldehydes pose a threat to these individuals by promoting degradation of wild-type BRCA2 protein, thereby predisposing them to genomic instability and perhaps to cancer.

      PubDate: 2017-06-06T13:04:20Z
       
  • Curbing Tregs’ (Lack of) Enthusiasm
    • Abstract: Publication date: 1 June 2017
      Source:Cell, Volume 169, Issue 6
      Author(s): Taha Merghoub, Jedd D. Wolchok
      In this issue, Overacre-Delgoffe et al. show that interferon gamma production by a subset of regulatory T cells in the tumor microenvironment triggers Treg instability locally and restores anti-tumor immunity.
      Teaser In this issue, Overacre-Delgoffe et al. show that interferon gamma production by a subset of regulatory T cells in the tumor microenvironment triggers Treg instability locally and restores anti-tumor immunity.

      PubDate: 2017-06-06T13:04:20Z
       
  • Genetic Control of Floral Architecture: Insights into Improving Crop Yield
    • Abstract: Publication date: 1 June 2017
      Source:Cell, Volume 169, Issue 6
      Author(s): Harry J. Klee
      Selection of plants with traits that are beneficial for cultivation and consumption has been a common practice for thousands of years; however, combination of these traits can be detrimental too, for instance by leading to undesirable branching and yield loss in tomato. The findings from Soyk et al. in this issue of Cell help understand how to bypass such negative effects and improve crop productivity.
      Teaser Selection of plants with traits that are beneficial for cultivation and consumption has been a common practice for thousands of years; however, combination of these traits can be detrimental too, for instance by leading to undesirable branching and yield loss in tomato. The findings from Soyk et al. in this issue of Cell help understand how to bypass such negative effects and improve crop productivity.

      PubDate: 2017-06-06T13:04:20Z
       
  • Wnt/β-Catenin Signaling, Disease, and Emerging Therapeutic Modalities
    • Abstract: Publication date: 1 June 2017
      Source:Cell, Volume 169, Issue 6
      Author(s): Roel Nusse, Hans Clevers
      The WNT signal transduction cascade is a main regulator of development throughout the animal kingdom. Wnts are also key drivers of most types of tissue stem cells in adult mammals. Unsurprisingly, mutated Wnt pathway components are causative to multiple growth-related pathologies and to cancer. Here, we describe the core Wnt/β-catenin signaling pathway, how it controls stem cells, and contributes to disease. Finally, we discuss strategies for Wnt-based therapies.
      Teaser The WNT pathway, a key regulator of development and stem cell function throughout the animal kingdom, is linked to a number of growth-related pathologies and to cancer.

      PubDate: 2017-06-06T13:04:20Z
       
  • Senescence in Health and Disease
    • Abstract: Publication date: 1 June 2017
      Source:Cell, Volume 169, Issue 6
      Author(s): Shenghui He, Norman E. Sharpless
      Many cellular stresses activate senescence, a persistent hyporeplicative state characterized in part by expression of the p16INK4a cell-cycle inhibitor. Senescent cell production occurs throughout life and plays beneficial roles in a variety of physiological and pathological processes including embryogenesis, wound healing, host immunity, and tumor suppression. Meanwhile, the steady accumulation of senescent cells with age also has adverse consequences. These non-proliferating cells occupy key cellular niches and elaborate pro-inflammatory cytokines, contributing to aging-related diseases and morbidity. This model suggests that the abundance of senescent cells in vivo predicts “molecular,” as opposed to chronologic, age and that senescent cell clearance may mitigate aging-associated pathology.
      Teaser Cellular senescence is important for ensuring normal development and organism fitness against diseases including cancer. Meanwhile, accumulation of senescent cells during aging can be detrimental, contributing to age-related diseases. This review discusses recent advances in understanding the functional significance of senescence in these contexts and the potential translational impact.

      PubDate: 2017-06-06T13:04:20Z
       
  • The Code for Facial Identity in the Primate Brain
    • Abstract: Publication date: 1 June 2017
      Source:Cell, Volume 169, Issue 6
      Author(s): Le Chang, Doris Y. Tsao
      Primates recognize complex objects such as faces with remarkable speed and reliability. Here, we reveal the brain’s code for facial identity. Experiments in macaques demonstrate an extraordinarily simple transformation between faces and responses of cells in face patches. By formatting faces as points in a high-dimensional linear space, we discovered that each face cell’s firing rate is proportional to the projection of an incoming face stimulus onto a single axis in this space, allowing a face cell ensemble to encode the location of any face in the space. Using this code, we could precisely decode faces from neural population responses and predict neural firing rates to faces. Furthermore, this code disavows the long-standing assumption that face cells encode specific facial identities, confirmed by engineering faces with drastically different appearance that elicited identical responses in single face cells. Our work suggests that other objects could be encoded by analogous metric coordinate systems. PaperClip
      Graphical abstract image Teaser Facial identity is encoded via a remarkably simple neural code that relies on the ability of neurons to distinguish facial features along specific axes in face space, disavowing the long-standing assumption that single face cells encode individual faces.

      PubDate: 2017-06-06T13:04:20Z
       
  • Noninvasive Deep Brain Stimulation via Temporally Interfering Electric
           Fields
    • Abstract: Publication date: 1 June 2017
      Source:Cell, Volume 169, Issue 6
      Author(s): Nir Grossman, David Bono, Nina Dedic, Suhasa B. Kodandaramaiah, Andrii Rudenko, Ho-Jun Suk, Antonino M. Cassara, Esra Neufeld, Niels Kuster, Li-Huei Tsai, Alvaro Pascual-Leone, Edward S. Boyden
      We report a noninvasive strategy for electrically stimulating neurons at depth. By delivering to the brain multiple electric fields at frequencies too high to recruit neural firing, but which differ by a frequency within the dynamic range of neural firing, we can electrically stimulate neurons throughout a region where interference between the multiple fields results in a prominent electric field envelope modulated at the difference frequency. We validated this temporal interference (TI) concept via modeling and physics experiments, and verified that neurons in the living mouse brain could follow the electric field envelope. We demonstrate the utility of TI stimulation by stimulating neurons in the hippocampus of living mice without recruiting neurons of the overlying cortex. Finally, we show that by altering the currents delivered to a set of immobile electrodes, we can steerably evoke different motor patterns in living mice.
      Graphical abstract image Teaser A noninvasive method for deep-brain stimulation may be a new approach for the treatment of neuropsychiatric diseases.

      PubDate: 2017-06-06T13:04:20Z
       
  • Cryo-EM Structure of a KCNQ1/CaM Complex Reveals Insights into Congenital
           Long QT Syndrome
    • Abstract: Publication date: 1 June 2017
      Source:Cell, Volume 169, Issue 6
      Author(s): Ji Sun, Roderick MacKinnon
      KCNQ1 is the pore-forming subunit of cardiac slow-delayed rectifier potassium (I Ks ) channels. Mutations in the kcnq1 gene are the leading cause of congenital long QT syndrome (LQTS). Here, we present the cryoelectron microscopy (cryo-EM) structure of a KCNQ1/calmodulin (CaM) complex. The conformation corresponds to an “uncoupled,” PIP2-free state of KCNQ1, with activated voltage sensors and a closed pore. Unique structural features within the S4-S5 linker permit uncoupling of the voltage sensor from the pore in the absence of PIP2. CaM contacts the KCNQ1 voltage sensor through a specific interface involving a residue on CaM that is mutated in a form of inherited LQTS. Using an electrophysiological assay, we find that this mutation on CaM shifts the KCNQ1 voltage-activation curve. This study describes one physiological form of KCNQ1, depolarized voltage sensors with a closed pore in the absence of PIP2, and reveals a regulatory interaction between CaM and KCNQ1 that may explain CaM-mediated LQTS.
      Graphical abstract image Teaser The cryo-EM structure of the potassium channel KCNQ1 in complex with calmodulin provides insight into the molecular underpinnings of congenital long QT syndrome.

      PubDate: 2017-06-06T13:04:20Z
       
  • The Mammalian Ribo-interactome Reveals Ribosome Functional Diversity and
           Heterogeneity
    • Abstract: Publication date: 1 June 2017
      Source:Cell, Volume 169, Issue 6
      Author(s): Deniz Simsek, Gerald C. Tiu, Ryan A. Flynn, Gun W. Byeon, Kathrin Leppek, Adele F. Xu, Howard Y. Chang, Maria Barna
      During eukaryotic evolution, ribosomes have considerably increased in size, forming a surface-exposed ribosomal RNA (rRNA) shell of unknown function, which may create an interface for yet uncharacterized interacting proteins. To investigate such protein interactions, we establish a ribosome affinity purification method that unexpectedly identifies hundreds of ribosome-associated proteins (RAPs) from categories including metabolism and cell cycle, as well as RNA- and protein-modifying enzymes that functionally diversify mammalian ribosomes. By further characterizing RAPs, we discover the presence of ufmylation, a metazoan-specific post-translational modification (PTM), on ribosomes and define its direct substrates. Moreover, we show that the metabolic enzyme, pyruvate kinase muscle (PKM), interacts with sub-pools of endoplasmic reticulum (ER)-associated ribosomes, exerting a non-canonical function as an RNA-binding protein in the translation of ER-destined mRNAs. Therefore, RAPs interconnect one of life’s most ancient molecular machines with diverse cellular processes, providing an additional layer of regulatory potential to protein expression.
      Graphical abstract image Teaser Functionally diverse proteins associate with mammalian ribosomes, and this repertoire differs with the subcellular localization of ribosomes and guides transcript-specific translation.

      PubDate: 2017-06-06T13:04:20Z
       
  • The Centrosome Is a Selective Condensate that Nucleates Microtubules by
           Concentrating Tubulin
    • Abstract: Publication date: 1 June 2017
      Source:Cell, Volume 169, Issue 6
      Author(s): Jeffrey B. Woodruff, Beatriz Ferreira Gomes, Per O. Widlund, Julia Mahamid, Alf Honigmann, Anthony A. Hyman
      Centrosomes are non-membrane-bound compartments that nucleate microtubule arrays. They consist of nanometer-scale centrioles surrounded by a micron-scale, dynamic assembly of protein called the pericentriolar material (PCM). To study how PCM forms a spherical compartment that nucleates microtubules, we reconstituted PCM-dependent microtubule nucleation in vitro using recombinant C. elegans proteins. We found that macromolecular crowding drives assembly of the key PCM scaffold protein SPD-5 into spherical condensates that morphologically and dynamically resemble in vivo PCM. These SPD-5 condensates recruited the microtubule polymerase ZYG-9 (XMAP215 homolog) and the microtubule-stabilizing protein TPXL-1 (TPX2 homolog). Together, these three proteins concentrated tubulin ∼4-fold over background, which was sufficient to reconstitute nucleation of microtubule asters in vitro. Our results suggest that in vivo PCM is a selective phase that organizes microtubule arrays through localized concentration of tubulin by microtubule effector proteins.
      Graphical abstract image Teaser In C. elegans, the pericentriolar material that surrounds centrioles is a phase-separated compartment that nucleates microtubule arrays through localized concentration of tubulin.

      PubDate: 2017-06-06T13:04:20Z
       
  • Structural Basis for Mitotic Centrosome Assembly in Flies
    • Abstract: Publication date: 1 June 2017
      Source:Cell, Volume 169, Issue 6
      Author(s): Zhe Feng, Anna Caballe, Alan Wainman, Steven Johnson, Andreas F.M. Haensele, Matthew A. Cottee, Paul T. Conduit, Susan M. Lea, Jordan W. Raff
      In flies, Centrosomin (Cnn) forms a phosphorylation-dependent scaffold that recruits proteins to the mitotic centrosome, but how Cnn assembles into a scaffold is unclear. We show that scaffold assembly requires conserved leucine zipper (LZ) and Cnn-motif 2 (CM2) domains that co-assemble into a 2:2 complex in vitro. We solve the crystal structure of the LZ:CM2 complex, revealing that both proteins form helical dimers that assemble into an unusual tetramer. A slightly longer version of the LZ can form micron-scale structures with CM2, whose assembly is stimulated by Plk1 phosphorylation in vitro. Mutating individual residues that perturb LZ:CM2 tetramer assembly perturbs the formation of these micron-scale assemblies in vitro and Cnn-scaffold assembly in vivo. Thus, Cnn molecules have an intrinsic ability to form large, LZ:CM2-interaction-dependent assemblies that are critical for mitotic centrosome assembly. These studies provide the first atomic insight into a molecular interaction required for mitotic centrosome assembly.
      Graphical abstract image Teaser Structural and biochemical analyses paint a new picture of how the pericentriolar material forms micron-scale structures that recruit PCM and nucleate microtubules.

      PubDate: 2017-06-06T13:04:20Z
       
  • A Class of Environmental and Endogenous Toxins Induces BRCA2
           Haploinsufficiency and Genome Instability
    • Abstract: Publication date: 1 June 2017
      Source:Cell, Volume 169, Issue 6
      Author(s): Shawn Lu Wen Tan, Saakshi Chadha, Yansheng Liu, Evelina Gabasova, David Perera, Karim Ahmed, Stephanie Constantinou, Xavier Renaudin, MiYoung Lee, Ruedi Aebersold, Ashok R. Venkitaraman
      Mutations truncating a single copy of the tumor suppressor, BRCA2, cause cancer susceptibility. In cells bearing such heterozygous mutations, we find that a cellular metabolite and ubiquitous environmental toxin, formaldehyde, stalls and destabilizes DNA replication forks, engendering structural chromosomal aberrations. Formaldehyde selectively depletes BRCA2 via proteasomal degradation, a mechanism of toxicity that affects very few additional cellular proteins. Heterozygous BRCA2 truncations, by lowering pre-existing BRCA2 expression, sensitize to BRCA2 haploinsufficiency induced by transient exposure to natural concentrations of formaldehyde. Acetaldehyde, an alcohol catabolite detoxified by ALDH2, precipitates similar effects. Ribonuclease H1 ameliorates replication fork instability and chromosomal aberrations provoked by aldehyde-induced BRCA2 haploinsufficiency, suggesting that BRCA2 inactivation triggers spontaneous mutagenesis during DNA replication via aberrant RNA-DNA hybrids (R-loops). These findings suggest a model wherein carcinogenesis in BRCA2 mutation carriers can be incited by compounds found pervasively in the environment and generated endogenously in certain tissues with implications for public health.
      Graphical abstract image Teaser Environmental and endogenous aldehydes contribute to genome instability and potentially tumorigenesis through selective degradation of BRCA2.

      PubDate: 2017-06-06T13:04:20Z
       
  • Interferon-γ Drives Treg Fragility to Promote Anti-tumor Immunity
    • Abstract: Publication date: Available online 25 May 2017
      Source:Cell
      Author(s): Abigail E. Overacre-Delgoffe, Maria Chikina, Rebekah E. Dadey, Hiroshi Yano, Erin A. Brunazzi, Gulidanna Shayan, William Horne, Jessica M. Moskovitz, Jay K. Kolls, Cindy Sander, Yongli Shuai, Daniel P. Normolle, John M. Kirkwood, Robert L. Ferris, Greg M. Delgoffe, Tullia C. Bruno, Creg J. Workman, Dario A.A. Vignali
      Regulatory T cells (Tregs) are a barrier to anti-tumor immunity. Neuropilin-1 (Nrp1) is required to maintain intratumoral Treg stability and function but is dispensable for peripheral immune tolerance. Treg-restricted Nrp1 deletion results in profound tumor resistance due to Treg functional fragility. Thus, identifying the basis for Nrp1 dependency and the key drivers of Treg fragility could help to improve immunotherapy for human cancer. We show that a high percentage of intratumoral NRP1+ Tregs correlates with poor prognosis in melanoma and head and neck squamous cell carcinoma. Using a mouse model of melanoma where Nrp1-deficient (Nrp1 –/–) and wild-type (Nrp1 +/+) Tregs can be assessed in a competitive environment, we find that a high proportion of intratumoral Nrp1 –/– Tregs produce interferon-γ (IFNγ), which drives the fragility of surrounding wild-type Tregs, boosts anti-tumor immunity, and facilitates tumor clearance. We also show that IFNγ-induced Treg fragility is required for response to anti-PD1, suggesting that cancer therapies promoting Treg fragility may be efficacious.
      Graphical abstract image Teaser Driving Treg fragility in the tumor microenvironment is critical for the efficacy of cancer checkpoint blockade therapy.

      PubDate: 2017-05-26T12:06:23Z
       
  • Ubiquitination-Deficient Mutations in Human Piwi Cause Male Infertility by
           Impairing Histone-to-Protamine Exchange during Spermiogenesis
    • Abstract: Publication date: Available online 25 May 2017
      Source:Cell
      Author(s): Lan-Tao Gou, Jun-Yan Kang, Peng Dai, Xin Wang, Feng Li, Shuang Zhao, Man Zhang, Min-Min Hua, Yi Lu, Yong Zhu, Zheng Li, Hong Chen, Li-Gang Wu, Dangsheng Li, Xiang-Dong Fu, Jinsong Li, Hui-Juan Shi, Mo-Fang Liu
      Genetic studies have elucidated critical roles of Piwi proteins in germline development in animals, but whether Piwi is an actual disease gene in human infertility remains unknown. We report germline mutations in human Piwi (Hiwi) in patients with azoospermia that prevent its ubiquitination and degradation. By modeling such mutations in Piwi (Miwi) knockin mice, we demonstrate that the genetic defects are directly responsible for male infertility. Mechanistically, we show that MIWI binds the histone ubiquitin ligase RNF8 in a Piwi-interacting RNA (piRNA)-independent manner, and MIWI stabilization sequesters RNF8 in the cytoplasm of late spermatids. The resulting aberrant sperm show histone retention, abnormal morphology, and severely compromised activity, which can be functionally rescued via blocking RNF8-MIWI interaction in spermatids with an RNF8-N peptide. Collectively, our findings identify Piwi as a factor in human infertility and reveal its role in regulating the histone-to-protamine exchange during spermiogenesis.
      Graphical abstract image Teaser Male infertility in mice and humans can result from mutations that stabilize the Piwi protein in late spermatids: sperm defects are due to aberrant histone retention, not piRNA misregulation.

      PubDate: 2017-05-26T12:06:23Z
       
  • Regulatory T Cells in Skin Facilitate Epithelial Stem Cell Differentiation
    • Abstract: Publication date: Available online 25 May 2017
      Source:Cell
      Author(s): Niwa Ali, Bahar Zirak, Robert Sanchez Rodriguez, Mariela L. Pauli, Hong-An Truong, Kevin Lai, Richard Ahn, Kaitlin Corbin, Margaret M. Lowe, Tiffany C. Scharschmidt, Keyon Taravati, Madeleine R. Tan, Roberto R. Ricardo-Gonzalez, Audrey Nosbaum, Marta Bertolini, Wilson Liao, Frank O. Nestle, Ralf Paus, George Cotsarelis, Abul K. Abbas, Michael D. Rosenblum
      The maintenance of tissue homeostasis is critically dependent on the function of tissue-resident immune cells and the differentiation capacity of tissue-resident stem cells (SCs). How immune cells influence the function of SCs is largely unknown. Regulatory T cells (Tregs) in skin preferentially localize to hair follicles (HFs), which house a major subset of skin SCs (HFSCs). Here, we mechanistically dissect the role of Tregs in HF and HFSC biology. Lineage-specific cell depletion revealed that Tregs promote HF regeneration by augmenting HFSC proliferation and differentiation. Transcriptional and phenotypic profiling of Tregs and HFSCs revealed that skin-resident Tregs preferentially express high levels of the Notch ligand family member, Jagged 1 (Jag1). Expression of Jag1 on Tregs facilitated HFSC function and efficient HF regeneration. Taken together, our work demonstrates that Tregs in skin play a major role in HF biology by promoting the function of HFSCs.
      Graphical abstract image Teaser Localized regulatory T cells (Tregs) regulate the hair follicle cycle by driving Notch-dependent stem cell proliferation and differentiation.

      PubDate: 2017-05-26T12:06:23Z
       
  • Silicon Valley Meets Biomedical Research in the Chan Zuckerberg Initiative
    • Abstract: Publication date: 18 May 2017
      Source:Cell, Volume 169, Issue 5
      Author(s): Diana Crow
      The Chan Zuckerberg Initiative, the philanthropy launched by Facebook CEO Mark Zuckerberg and his wife Priscilla Chan, drew attention with its stated goal of helping to “cure, manage, or treat all diseases” by the end of the century. They intend to do it through funding basic research and addressing gaps in biomedical technology.
      Teaser The Chan Zuckerberg Initiative, the philanthropy launched by Facebook CEO Mark Zuckerberg and his wife Priscilla Chan, drew attention with its stated goal of helping to “cure, manage, or treat all diseases” by the end of the century. They intend to do it through funding basic research and addressing gaps in biomedical technology.

      PubDate: 2017-05-22T12:02:33Z
       
  • Big Questions in Microbiology
    • Abstract: Publication date: 18 May 2017
      Source:Cell, Volume 169, Issue 5


      PubDate: 2017-05-22T12:02:33Z
       
  • Ebolavirus’s Foibles
    • Abstract: Publication date: 18 May 2017
      Source:Cell, Volume 169, Issue 5
      Author(s): Seiya Yamayoshi, Yoshihiro Kawaoka
      Ebola virus disease poses a global health threat. Here, two studies by Wec et al. and Zhao et al. identified vulnerability in an internal fusion loop of an ebolavirus glycoprotein. Monoclonal antibodies elicited from immunization and isolated from a human survivor that recognized epitopes in this area neutralized all five ebolaviruses, guiding the development of a pan-ebolavirus immunotherapy.
      Teaser Ebola virus disease poses a global health threat. Here, two studies by Wec et al. and Zhao et al. identified vulnerability in an internal fusion loop of an ebolavirus glycoprotein. Monoclonal antibodies elicited from immunization and isolated from a human survivor that recognized epitopes in this area neutralized all five ebolaviruses, guiding the development of a pan-ebolavirus immunotherapy.

      PubDate: 2017-05-22T12:02:33Z
       
  • How Does Familiarity Breed Contempt?
    • Abstract: Publication date: 18 May 2017
      Source:Cell, Volume 169, Issue 5
      Author(s): Kevin Mann, Thomas R. Clandinin
      Classifying sensory experiences as either novel or familiar represents a fundamental challenge to neural processing. In this issue of Cell, Hattori et al. describe a circuit mechanism by which a novel stimulus that initially interests a fruit fly turns into a familiar one.
      Teaser Classifying sensory experiences as either novel or familiar represents a fundamental challenge to neural processing. In this issue of Cell, Hattori et al. describe a circuit mechanism by which a novel stimulus that initially interests a fruit fly turns into a familiar one.

      PubDate: 2017-05-22T12:02:33Z
       
  • Lung Cancer: A Wily Genetic Opponent
    • Abstract: Publication date: 18 May 2017
      Source:Cell, Volume 169, Issue 5
      Author(s): Peggy P. Hsu, Alice T. Shaw
      In two companion reports, the TRACERx consortium investigates tumor heterogeneity and evolution in early-stage non-small cell lung cancer. The studies highlight the prognostic value of copy-number heterogeneity assessment in tumor biopsies and circulating tumor DNA detection in plasma and suggest that tracking the evolution of lung cancers might aid clinical practice.
      Teaser In two companion reports, the TRACERx consortium investigates tumor heterogeneity and evolution in early-stage non-small cell lung cancer. The studies highlight the prognostic value of copy-number heterogeneity assessment in tumor biopsies and circulating tumor DNA detection in plasma and suggest that tracking the evolution of lung cancers might aid clinical practice.

      PubDate: 2017-05-22T12:02:33Z
       
  • Lamina-Associated Domains: Links with Chromosome Architecture,
           Heterochromatin, and Gene Repression
    • Abstract: Publication date: 18 May 2017
      Source:Cell, Volume 169, Issue 5
      Author(s): Bas van Steensel, Andrew S. Belmont
      In metazoan cell nuclei, hundreds of large chromatin domains are in close contact with the nuclear lamina. Such lamina-associated domains (LADs) are thought to help organize chromosomes inside the nucleus and have been associated with gene repression. Here, we discuss the properties of LADs, the molecular mechanisms that determine their association with the nuclear lamina, their dynamic links with other nuclear compartments, and their proposed roles in gene regulation.
      Teaser Chromatin domains associated with the nuclear lamina have dynamic links to other nuclear compartments and regulate cellular gene expression.

      PubDate: 2017-05-22T12:02:33Z
       
  • The Logic of the 26S Proteasome
    • Abstract: Publication date: 18 May 2017
      Source:Cell, Volume 169, Issue 5
      Author(s): Galen Andrew Collins, Alfred L. Goldberg
      The ubiquitin proteasome pathway is responsible for most of the protein degradation in mammalian cells. Rates of degradation by this pathway have generally been assumed to be determined by rates of ubiquitylation. However, recent studies indicate that proteasome function is also tightly regulated and determines whether a ubiquitylated protein is destroyed or deubiquitylated and survives longer. This article reviews recent advances in our understanding of the proteasome's multistep ATP-dependent mechanism, its biochemical and structural features that ensure efficient proteolysis and ubiquitin recycling while preventing nonselective proteolysis, and the regulation of proteasome activity by interacting proteins and subunit modifications, especially phosphorylation.
      Teaser The proteasome is responsible for most protein degradation in mammalian cells. Recent advances in the field now provide a greater understanding of its mode of action and regulation.

      PubDate: 2017-05-22T12:02:33Z
       
  • Bypassing Negative Epistasis on Yield in Tomato Imposed by a Domestication
           Gene
    • Abstract: Publication date: Available online 18 May 2017
      Source:Cell
      Author(s): Sebastian Soyk, Zachary H. Lemmon, Matan Oved, Josef Fisher, Katie L. Liberatore, Soon Ju Park, Anna Goren, Ke Jiang, Alexis Ramos, Esther van der Knaap, Joyce Van Eck, Dani Zamir, Yuval Eshed, Zachary B. Lippman
      Selection for inflorescence architecture with improved flower production and yield is common to many domesticated crops. However, tomato inflorescences resemble wild ancestors, and breeders avoided excessive branching because of low fertility. We found branched variants carry mutations in two related transcription factors that were selected independently. One founder mutation enlarged the leaf-like organs on fruits and was selected as fruit size increased during domestication. The other mutation eliminated the flower abscission zone, providing “jointless” fruit stems that reduced fruit dropping and facilitated mechanical harvesting. Stacking both beneficial traits caused undesirable branching and sterility due to epistasis, which breeders overcame with suppressors. However, this suppression restricted the opportunity for productivity gains from weak branching. Exploiting natural and engineered alleles for multiple family members, we achieved a continuum of inflorescence complexity that allowed breeding of higher-yielding hybrids. Characterizing and neutralizing similar cases of negative epistasis could improve productivity in many agricultural organisms. Video
      Graphical abstract image Teaser Why did a crop domestication gene hinder breeding with a modern breeding gene responsible for the beneficial “jointless” trait in tomato, and how can this genetic interaction be overcome and exploited?

      PubDate: 2017-05-22T12:02:33Z
       
  • Vitamin A-Retinoic Acid Signaling Regulates Hematopoietic Stem Cell
           Dormancy
    • Abstract: Publication date: Available online 4 May 2017
      Source:Cell
      Author(s): Nina Cabezas-Wallscheid, Florian Buettner, Pia Sommerkamp, Daniel Klimmeck, Luisa Ladel, Frederic B. Thalheimer, Daniel Pastor-Flores, Leticia P. Roma, Simon Renders, Petra Zeisberger, Adriana Przybylla, Katharina Schönberger, Roberta Scognamiglio, Sandro Altamura, Carolina M. Florian, Malak Fawaz, Dominik Vonficht, Melania Tesio, Paul Collier, Dinko Pavlinic, Hartmut Geiger, Timm Schroeder, Vladimir Benes, Tobias P. Dick, Michael A. Rieger, Oliver Stegle, Andreas Trumpp
      Dormant hematopoietic stem cells (dHSCs) are atop the hematopoietic hierarchy. The molecular identity of dHSCs and the mechanisms regulating their maintenance or exit from dormancy remain uncertain. Here, we use single-cell RNA sequencing (RNA-seq) analysis to show that the transition from dormancy toward cell-cycle entry is a continuous developmental path associated with upregulation of biosynthetic processes rather than a stepwise progression. In addition, low Myc levels and high expression of a retinoic acid program are characteristic for dHSCs. To follow the behavior of dHSCs in situ, a Gprc5c-controlled reporter mouse was established. Treatment with all-trans retinoic acid antagonizes stress-induced activation of dHSCs by restricting protein translation and levels of reactive oxygen species (ROS) and Myc. Mice maintained on a vitamin A-free diet lose HSCs and show a disrupted re-entry into dormancy after exposure to inflammatory stress stimuli. Our results highlight the impact of dietary vitamin A on the regulation of cell-cycle-mediated stem cell plasticity.
      Graphical abstract image Teaser Metabolic inputs control the entry and exit of hematopoietic stem cells from dormancy and suggest the potential application of vitamin A in hematopoietic disorders and leukemias.

      PubDate: 2017-05-07T12:12:57Z
       
 
 
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