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Journal Cover Cell
  [SJR: 28.188]   [H-I: 616]   [753 followers]  Follow
    
   Full-text available via subscription Subscription journal
   ISSN (Print) 0092-8674 - ISSN (Online) 1097-4172
   Published by Elsevier Homepage  [3031 journals]
  • 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
       
  • The U6 snRNA m6A Methyltransferase METTL16 Regulates SAM Synthetase Intron
           Retention
    • Abstract: Publication date: 18 May 2017
      Source:Cell, Volume 169, Issue 5
      Author(s): Kathryn E. Pendleton, Beibei Chen, Kuanqing Liu, Olga V. Hunter, Yang Xie, Benjamin P. Tu, Nicholas K. Conrad
      Maintenance of proper levels of the methyl donor S-adenosylmethionine (SAM) is critical for a wide variety of biological processes. We demonstrate that the N6-adenosine methyltransferase METTL16 regulates expression of human MAT2A, which encodes the SAM synthetase expressed in most cells. Upon SAM depletion by methionine starvation, cells induce MAT2A expression by enhanced splicing of a retained intron. Induction requires METTL16 and its methylation substrate, a vertebrate conserved hairpin (hp1) in the MAT2A 3′ UTR. Increasing METTL16 occupancy on the MAT2A 3′ UTR is sufficient to induce efficient splicing. We propose that, under SAM-limiting conditions, METTL16 occupancy on hp1 increases due to inefficient enzymatic turnover, which promotes MAT2A splicing. We further show that METTL16 is the long-unknown methyltransferase for the U6 spliceosomal small nuclear RNA (snRNA). These observations suggest that the conserved U6 snRNA methyltransferase evolved an additional function in vertebrates to regulate SAM homeostasis.
      Graphical abstract image Teaser An RNA methyltransferase controls cellular SAM levels through post-transcriptional regulatory feedback.

      PubDate: 2017-05-22T12:02:33Z
       
  • Regulated Intron Removal Integrates Motivational State and Experience
    • Abstract: Publication date: 18 May 2017
      Source:Cell, Volume 169, Issue 5
      Author(s): Jason Gill, Younshim Park, J.P. McGinnis, Consuelo Perez-Sanchez, Marco Blanchette, Kausik Si
      Myriad experiences produce transient memory, yet, contingent on the internal state of the organism and the saliency of the experience, only some memories persist over time. How experience and internal state influence the duration of memory at the molecular level remains unknown. A self-assembled aggregated state of Drosophila Orb2A protein is required specifically for long-lasting memory. We report that in the adult fly brain the mRNA encoding Orb2A protein exists in an unspliced non-protein-coding form. The convergence of experience and internal drive transiently increases the spliced protein-coding Orb2A mRNA. A screen identified pasilla, the fly ortholog of mammalian Nova-1/2, as a mediator of Orb2A mRNA processing. A single-nucleotide substitution in the intronic region that reduces Pasilla binding and intron removal selectively impairs long-term memory. We posit that pasilla-mediated processing of unspliced Orb2A mRNA integrates experience and internal state to control Orb2A protein abundance and long-term memory formation.
      Graphical abstract image Teaser The removal of a retained intron in Orb2A couples internal states, such as starvation, to transient external stimuli, such as food and odor, allowing the formation of long-lasting memory in Drosophila.

      PubDate: 2017-05-22T12:02:33Z
       
  • Antibodies from a Human Survivor Define Sites of Vulnerability for Broad
           Protection against Ebolaviruses
    • Abstract: Publication date: 18 May 2017
      Source:Cell, Volume 169, Issue 5
      Author(s): Anna Z. Wec, Andrew S. Herbert, Charles D. Murin, Elisabeth K. Nyakatura, Dafna M. Abelson, J. Maximilian Fels, Shihua He, Rebekah M. James, Marc-Antoine de La Vega, Wenjun Zhu, Russell R. Bakken, Eileen Goodwin, Hannah L. Turner, Rohit K. Jangra, Larry Zeitlin, Xiangguo Qiu, Jonathan R. Lai, Laura M. Walker, Andrew B. Ward, John M. Dye, Kartik Chandran, Zachary A. Bornholdt
      Experimental monoclonal antibody (mAb) therapies have shown promise for treatment of lethal Ebola virus (EBOV) infections, but their species-specific recognition of the viral glycoprotein (GP) has limited their use against other divergent ebolaviruses associated with human disease. Here, we mined the human immune response to natural EBOV infection and identified mAbs with exceptionally potent pan-ebolavirus neutralizing activity and protective efficacy against three virulent ebolaviruses. These mAbs recognize an inter-protomer epitope in the GP fusion loop, a critical and conserved element of the viral membrane fusion machinery, and neutralize viral entry by targeting a proteolytically primed, fusion-competent GP intermediate (GPCL) generated in host cell endosomes. Only a few somatic hypermutations are required for broad antiviral activity, and germline-approximating variants display enhanced GPCL recognition, suggesting that such antibodies could be elicited more efficiently with suitably optimized GP immunogens. Our findings inform the development of both broadly effective immunotherapeutics and vaccines against filoviruses.
      Graphical abstract image Teaser Characterization of human broadly neutralizing antibodies active against all five species of ebolaviruses highlights the fusion loop region of the viral glycoprotein as a promising vaccine target.

      PubDate: 2017-05-22T12:02:33Z
       
  • Immunization-Elicited Broadly Protective Antibody Reveals Ebolavirus
           Fusion Loop as a Site of Vulnerability
    • Abstract: Publication date: 18 May 2017
      Source:Cell, Volume 169, Issue 5
      Author(s): Xuelian Zhao, Katie A. Howell, Shihua He, Jennifer M. Brannan, Anna Z. Wec, Edgar Davidson, Hannah L. Turner, Chi-I. Chiang, Lin Lei, J. Maximilian Fels, Hong Vu, Sergey Shulenin, Ashley N. Turonis, Ana I. Kuehne, Guodong Liu, Mi Ta, Yimeng Wang, Christopher Sundling, Yongli Xiao, Jennifer S. Spence, Benjamin J. Doranz, Frederick W. Holtsberg, Andrew B. Ward, Kartik Chandran, John M. Dye, Xiangguo Qiu, Yuxing Li, M. Javad Aman
      While neutralizing antibodies are highly effective against ebolavirus infections, current experimental ebolavirus vaccines primarily elicit species-specific antibody responses. Here, we describe an immunization-elicited macaque antibody (CA45) that clamps the internal fusion loop with the N terminus of the ebolavirus glycoproteins (GPs) and potently neutralizes Ebola, Sudan, Bundibugyo, and Reston viruses. CA45, alone or in combination with an antibody that blocks receptor binding, provided full protection against all pathogenic ebolaviruses in mice, guinea pigs, and ferrets. Analysis of memory B cells from the immunized macaque suggests that elicitation of broadly neutralizing antibodies (bNAbs) for ebolaviruses is possible but difficult, potentially due to the rarity of bNAb clones and their precursors. Unexpectedly, germline-reverted CA45, while exhibiting negligible binding to full-length GP, bound a proteolytically remodeled GP with picomolar affinity, suggesting that engineered ebolavirus vaccines could trigger rare bNAb precursors more robustly. These findings have important implications for developing pan-ebolavirus vaccine and immunotherapeutic cocktails.
      Graphical abstract image Teaser Characterization of an immunization-induced broadly neutralizing antibody in macaques against ebolaviruses highlights the fusion loop region of the viral glycoprotein as a promising vaccine target.

      PubDate: 2017-05-22T12:02:33Z
       
  • Widespread Influence of 3′-End Structures on Mammalian mRNA
           Processing and Stability
    • Abstract: Publication date: 18 May 2017
      Source:Cell, Volume 169, Issue 5
      Author(s): Xuebing Wu, David P. Bartel
      The physiological relevance of structures within mammalian mRNAs has been elusive, as these mRNAs are less folded in cells than in vitro and have predicted secondary structures no more stable than those of random sequences. Here, we investigate the possibility that mRNA structures facilitate the 3′-end processing of thousands of human mRNAs by juxtaposing poly(A) signals (PASs) and cleavage sites that are otherwise too far apart. We find that RNA structures are predicted to be more prevalent within these extended 3′-end regions than within PAS-upstream regions and indeed are substantially more folded within cells, as determined by intracellular probing. Analyses of thousands of ectopically expressed variants demonstrate that this folding both enhances processing and increases mRNA metabolic stability. Even folds with predicted stabilities resembling those of random sequences can enhance processing. Structure-controlled processing can also regulate neighboring gene expression. Thus, RNA structure has widespread roles in mammalian mRNA biogenesis and metabolism.
      Graphical abstract image Teaser Folded structures near 3′ ends enhance both the maturation and the stability of many human mRNAs.

      PubDate: 2017-05-22T12:02:33Z
       
  • Targeted Degradation of CTCF Decouples Local Insulation of Chromosome
           Domains from Genomic Compartmentalization
    • Abstract: Publication date: 18 May 2017
      Source:Cell, Volume 169, Issue 5
      Author(s): Elphège P. Nora, Anton Goloborodko, Anne-Laure Valton, Johan H. Gibcus, Alec Uebersohn, Nezar Abdennur, Job Dekker, Leonid A. Mirny, Benoit G. Bruneau
      The molecular mechanisms underlying folding of mammalian chromosomes remain poorly understood. The transcription factor CTCF is a candidate regulator of chromosomal structure. Using the auxin-inducible degron system in mouse embryonic stem cells, we show that CTCF is absolutely and dose-dependently required for looping between CTCF target sites and insulation of topologically associating domains (TADs). Restoring CTCF reinstates proper architecture on altered chromosomes, indicating a powerful instructive function for CTCF in chromatin folding. CTCF remains essential for TAD organization in non-dividing cells. Surprisingly, active and inactive genome compartments remain properly segregated upon CTCF depletion, revealing that compartmentalization of mammalian chromosomes emerges independently of proper insulation of TADs. Furthermore, our data support that CTCF mediates transcriptional insulator function through enhancer blocking but not as a direct barrier to heterochromatin spreading. Beyond defining the functions of CTCF in chromosome folding, these results provide new fundamental insights into the rules governing mammalian genome organization.
      Graphical abstract image Teaser Dissecting out the roles of CTCF on genome looping, organization into TADs, and overall chromatin compartmentalization reveals fine layers of regulation.

      PubDate: 2017-05-22T12:02:33Z
       
  • Modeling Rett Syndrome Using TALEN-Edited MECP2 Mutant Cynomolgus Monkeys
    • Abstract: Publication date: 18 May 2017
      Source:Cell, Volume 169, Issue 5
      Author(s): Yongchang Chen, Juehua Yu, Yuyu Niu, Dongdong Qin, Hailiang Liu, Gang Li, Yingzhou Hu, Jiaojian Wang, Yi Lu, Yu Kang, Yong Jiang, Kunhua Wu, Siguang Li, Jingkuan Wei, Jing He, Junbang Wang, Xiaojing Liu, Yuping Luo, Chenyang Si, Raoxian Bai, Kunshan Zhang, Jie Liu, Shaoyong Huang, Zhenzhen Chen, Shuang Wang, Xiaoying Chen, Xinhua Bao, Qingping Zhang, Fuxing Li, Rui Geng, Aibin Liang, Dinggang Shen, Tianzi Jiang, Xintian Hu, Yuanye Ma, Weizhi Ji, Yi Eve Sun
      Gene-editing technologies have made it feasible to create nonhuman primate models for human genetic disorders. Here, we report detailed genotypes and phenotypes of TALEN-edited MECP2 mutant cynomolgus monkeys serving as a model for a neurodevelopmental disorder, Rett syndrome (RTT), which is caused by loss-of-function mutations in the human MECP2 gene. Male mutant monkeys were embryonic lethal, reiterating that RTT is a disease of females. Through a battery of behavioral analyses, including primate-unique eye-tracking tests, in combination with brain imaging via MRI, we found a series of physiological, behavioral, and structural abnormalities resembling clinical manifestations of RTT. Moreover, blood transcriptome profiling revealed that mutant monkeys resembled RTT patients in immune gene dysregulation. Taken together, the stark similarity in phenotype and/or endophenotype between monkeys and patients suggested that gene-edited RTT founder monkeys would be of value for disease mechanistic studies as well as development of potential therapeutic interventions for RTT.
      Graphical abstract image Teaser TALEN-edited MeCP2 mutant monkeys share phenotypes with Rett syndrome patients, providing a valuable model for studying disease mechanisms and for the development of potential therapeutics.

      PubDate: 2017-05-22T12:02:33Z
       
  • SnapShot: Nucleo-cytoskeletal Interactions
    • Abstract: Publication date: 18 May 2017
      Source:Cell, Volume 169, Issue 5
      Author(s): Cátia S. Janota, Francisco J. Calero-Cuenca, Judite Costa, Edgar R. Gomes
      The nucleus is connected to the cytoskeleton, and these connections are involved in multiple functions such as nuclear positioning, shape and stiffness, cytoskeleton organization, mechanotransduction, gene expression, chromosome positioning, DNA repair, and cell migration.
      Teaser The nucleus is connected to the cytoskeleton, and these connections are involved in multiple functions such as nuclear positioning, shape and stiffness, cytoskeleton organization, mechanotransduction, gene expression, chromosome positioning, DNA repair, and cell migration.

      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
       
  • Tracing the Enterococci from Paleozoic Origins to the Hospital
    • Abstract: Publication date: Available online 11 May 2017
      Source:Cell
      Author(s): François Lebreton, Abigail L. Manson, Jose T. Saavedra, Timothy J. Straub, Ashlee M. Earl, Michael S. Gilmore
      We examined the evolutionary history of leading multidrug resistant hospital pathogens, the enterococci, to their origin hundreds of millions of years ago. Our goal was to understand why, among the vast diversity of gut flora, enterococci are so well adapted to the modern hospital environment. Molecular clock estimation, together with analysis of their environmental distribution, phenotypic diversity, and concordance with host fossil records, place the origins of the enterococci around the time of animal terrestrialization, 425–500 mya. Speciation appears to parallel the diversification of hosts, including the rapid emergence of new enterococcal species following the End Permian Extinction. Major drivers of speciation include changing carbohydrate availability in the host gut. Life on land would have selected for the precise traits that now allow pathogenic enterococci to survive desiccation, starvation, and disinfection in the modern hospital, foreordaining their emergence as leading hospital pathogens.
      Graphical abstract image Teaser Why, among the vast diversity of gut microbiota, have enterococci become so well adapted to the modern hospital environment?

      PubDate: 2017-05-17T01:48:14Z
       
  • An Atomic Structure of the Human Spliceosome
    • Abstract: Publication date: Available online 11 May 2017
      Source:Cell
      Author(s): Xiaofeng Zhang, Chuangye Yan, Jing Hang, Lorenzo I. Finci, Jianlin Lei, Yigong Shi
      Mechanistic understanding of pre-mRNA splicing requires detailed structural information on various states of the spliceosome. Here we report the cryo electron microscopy (cryo-EM) structure of the human spliceosome just before exon ligation (the C∗ complex) at an average resolution of 3.76 Å. The splicing factor Prp17 stabilizes the active site conformation. The step II factor Slu7 adopts an extended conformation, binds Prp8 and Cwc22, and is poised for selection of the 3′-splice site. Remarkably, the intron lariat traverses through a positively charged central channel of RBM22; this unusual organization suggests mechanisms of intron recruitment, confinement, and release. The protein PRKRIP1 forms a 100-Å α helix linking the distant U2 snRNP to the catalytic center. A 35-residue fragment of the ATPase/helicase Prp22 latches onto Prp8, and the quaternary exon junction complex (EJC) recognizes upstream 5′-exon sequences and associates with Cwc22 and the GTPase Snu114. These structural features reveal important mechanistic insights into exon ligation.
      Graphical abstract image Teaser The first atomic structure of human spliceosome reveals important insights into exon ligation.

      PubDate: 2017-05-17T01:48:14Z
       
  • Representations of Novelty and Familiarity in a Mushroom Body Compartment
    • Abstract: Publication date: Available online 11 May 2017
      Source:Cell
      Author(s): Daisuke Hattori, Yoshinori Aso, Kurtis J. Swartz, Gerald M. Rubin, L.F. Abbott, Richard Axel
      Animals exhibit a behavioral response to novel sensory stimuli about which they have no prior knowledge. We have examined the neural and behavioral correlates of novelty and familiarity in the olfactory system of Drosophila. Novel odors elicit strong activity in output neurons (MBONs) of the α′3 compartment of the mushroom body that is rapidly suppressed upon repeated exposure to the same odor. This transition in neural activity upon familiarization requires odor-evoked activity in the dopaminergic neuron innervating this compartment. Moreover, exposure of a fly to novel odors evokes an alerting response that can also be elicited by optogenetic activation of α′3 MBONs. Silencing these MBONs eliminates the alerting behavior. These data suggest that the α′3 compartment plays a causal role in the behavioral response to novel and familiar stimuli as a consequence of dopamine-mediated plasticity at the Kenyon cell-MBONα′3 synapse.
      Graphical abstract image Teaser The Drosophila mushroom body, a brain region that functions in classical learning, also helps flies identify novel stimuli and become accustomed to them.

      PubDate: 2017-05-17T01:48:14Z
       
  • Metabolic Phenotypes of Response to Vaccination in Humans
    • Abstract: Publication date: Available online 11 May 2017
      Source:Cell
      Author(s): Shuzhao Li, Nicole L. Sullivan, Nadine Rouphael, Tianwei Yu, Sophia Banton, Mohan S. Maddur, Megan McCausland, Christopher Chiu, Jennifer Canniff, Sheri Dubey, Ken Liu, ViLinh Tran, Thomas Hagan, Sai Duraisingham, Andreas Wieland, Aneesh K. Mehta, Jennifer A. Whitaker, Shankar Subramaniam, Dean P. Jones, Alessandro Sette, Kalpit Vora, Adriana Weinberg, Mark J. Mulligan, Helder I. Nakaya, Myron Levin, Rafi Ahmed, Bali Pulendran
      Herpes zoster (shingles) causes significant morbidity in immune compromised hosts and older adults. Whereas a vaccine is available for prevention of shingles, its efficacy declines with age. To help to understand the mechanisms driving vaccinal responses, we constructed a multiscale, multifactorial response network (MMRN) of immunity in healthy young and older adults immunized with the live attenuated shingles vaccine Zostavax. Vaccination induces robust antigen-specific antibody, plasmablasts, and CD4+ T cells yet limited CD8+ T cell and antiviral responses. The MMRN reveals striking associations between orthogonal datasets, such as transcriptomic and metabolomics signatures, cell populations, and cytokine levels, and identifies immune and metabolic correlates of vaccine immunity. Networks associated with inositol phosphate, glycerophospholipids, and sterol metabolism are tightly coupled with immunity. Critically, the sterol regulatory binding protein 1 and its targets are key integrators of antibody and T follicular cell responses. Our approach is broadly applicable to study human immunity and can help to identify predictors of efficacy as well as mechanisms controlling immunity to vaccination.
      Graphical abstract image Teaser An integrated metabolic response underlies the immune response to shingles vaccine in humans.

      PubDate: 2017-05-17T01:48:14Z
       
  • The Right Tool for the Job
    • Abstract: Publication date: 4 May 2017
      Source:Cell, Volume 169, Issue 4
      Author(s): Lara Szewczak


      PubDate: 2017-05-07T12:12:57Z
       
  • Don’t Stop Re-healin’! Cancer as an Ongoing Stem Cell Affair
    • Abstract: Publication date: 4 May 2017
      Source:Cell, Volume 169, Issue 4
      Author(s): Samuel P. Rowbotham, Carla F. Kim
      Tumors have long been suspected of hijacking stem cell mechanisms used for tissue maintenance and repair. Ge et al. now show that skin tumors exhibit merged chromatin profiles from distinct stem cell lineages. This “lineage infidelity” recreates a state akin to transient wound repair that persists to maintain uncontrolled growth.
      Teaser Tumors have long been suspected of hijacking stem cell mechanisms used for tissue maintenance and repair. Ge et al. now show that skin tumors exhibit merged chromatin profiles from distinct stem cell lineages. This “lineage infidelity” recreates a state akin to transient wound repair that persists to maintain uncontrolled growth.

      PubDate: 2017-05-07T12:12:57Z
       
  • Ribosomes Need Straight A’s to Sleep
    • Abstract: Publication date: 4 May 2017
      Source:Cell, Volume 169, Issue 4
      Author(s): Samuel B. Sondalle, Susan J. Baserga
      Like falling asleep and waking up, many biological processes in mammals cycle in a diurnal fashion. Now, Sinturel et al. demonstrate that diurnal size changes in the liver require eating during a mouse’s normal awake time and that these size changes are controlled by a nuclear mechanism that modulates ribosome production.
      Teaser Like falling asleep and waking up, many biological processes in mammals cycle in a diurnal fashion. Now, Sinturel et al. demonstrate that diurnal size changes in the liver require eating during a mouse’s normal awake time and that these size changes are controlled by a nuclear mechanism that modulates ribosome production.

      PubDate: 2017-05-07T12:12:57Z
       
  • Heavy Metal Enlightens Tumor Immunity
    • Abstract: Publication date: 4 May 2017
      Source:Cell, Volume 169, Issue 4
      Author(s): Jonathan H. Chen, Karin Pelka, Nir Hacohen
      A deep understanding of the immune landscape in human cancer is essential for guiding the development of immunotherapy to benefit more patients with long-lasting efficacy. Now, two studies from Lavin et al. and Chevrier et al. employ mass cytometry to study immune infiltrates in lung adenocarcinoma and clear cell renal cell carcinoma, respectively.
      Teaser A deep understanding of the immune landscape in human cancer is essential for guiding the development of immunotherapy to benefit more patients with long-lasting efficacy. Now, two studies from Lavin et al. and Chevrier et al. employ mass cytometry to study immune infiltrates in lung adenocarcinoma and clear cell renal cell carcinoma, respectively.

      PubDate: 2017-05-07T12:12:57Z
       
  • Metabolic Instruction of Immunity
    • Abstract: Publication date: 4 May 2017
      Source:Cell, Volume 169, Issue 4
      Author(s): Michael D. Buck, Ryan T. Sowell, Susan M. Kaech, Erika L. Pearce
      Choices have consequences. Immune cells survey and migrate throughout the body and sometimes take residence in niche environments with distinct communities of cells, extracellular matrix, and nutrients that may differ from those in which they matured. Imbedded in immune cell physiology are metabolic pathways and metabolites that not only provide energy and substrates for growth and survival, but also instruct effector functions, differentiation, and gene expression. This review of immunometabolism will reference the most recent literature to cover the choices that environments impose on the metabolism and function of immune cells and highlight their consequences during homeostasis and disease.
      Teaser Immune cells are exposed to distinct environments and nutrients that influence metabolism that, in turn, instruct their effector functions, differentiation, and gene expression.

      PubDate: 2017-05-07T12:12:57Z
       
  • Communication in the Phytobiome
    • Abstract: Publication date: 4 May 2017
      Source:Cell, Volume 169, Issue 4
      Author(s): Jan E. Leach, Lindsay R. Triplett, Cristiana T. Argueso, Pankaj Trivedi
      The phytobiome is composed of plants, their environment, and diverse interacting microscopic and macroscopic organisms, which together influence plant health and productivity. These organisms form complex networks that are established and regulated through nutrient cycling, competition, antagonism, and chemical communication mediated by a diverse array of signaling molecules. Integration of knowledge of signaling mechanisms with that of phytobiome members and their networks will lead to a new understanding of the fate and significance of these signals at the ecosystem level. Such an understanding could lead to new biological, chemical, and breeding strategies to improve crop health and productivity.
      Teaser The phytobiome, a network composed of plants, their environment, and the composite micro- and macro-organisms within, influences plant health and crop productivity through a myriad of complex communication mechanisms.

      PubDate: 2017-05-07T12:12:57Z
       
  • Recurrent Potent Human Neutralizing Antibodies to Zika Virus in Brazil and
           Mexico
    • Abstract: Publication date: 4 May 2017
      Source:Cell, Volume 169, Issue 4
      Author(s): Davide F. Robbiani, Leonia Bozzacco, Jennifer R. Keeffe, Ricardo Khouri, Priscilla C. Olsen, Anna Gazumyan, Dennis Schaefer-Babajew, Santiago Avila-Rios, Lilian Nogueira, Roshni Patel, Stephanie A. Azzopardi, Lion F.K. Uhl, Mohsan Saeed, Edgar E. Sevilla-Reyes, Marianna Agudelo, Kai-Hui Yao, Jovana Golijanin, Harry B. Gristick, Yu E. Lee, Arlene Hurley, Marina Caskey, Joy Pai, Thiago Oliveira, Elsio A. Wunder, Gielson Sacramento, Nivison Nery, Cibele Orge, Federico Costa, Mitermayer G. Reis, Neena M. Thomas, Thomas Eisenreich, Daniel M. Weinberger, Antonio R.P. de Almeida, Anthony P. West, Charles M. Rice, Pamela J. Bjorkman, Gustavo Reyes-Teran, Albert I. Ko, Margaret R. MacDonald, Michel C. Nussenzweig
      Antibodies to Zika virus (ZIKV) can be protective. To examine the antibody response in individuals who develop high titers of anti-ZIKV antibodies, we screened cohorts in Brazil and Mexico for ZIKV envelope domain III (ZEDIII) binding and neutralization. We find that serologic reactivity to dengue 1 virus (DENV1) EDIII before ZIKV exposure is associated with increased ZIKV neutralizing titers after exposure. Antibody cloning shows that donors with high ZIKV neutralizing antibody titers have expanded clones of memory B cells that express the same immunoglobulin VH3-23/VK1-5 genes. These recurring antibodies cross-react with DENV1, but not other flaviviruses, neutralize both DENV1 and ZIKV, and protect mice against ZIKV challenge. Structural analyses reveal the mechanism of recognition of the ZEDIII lateral ridge by VH3-23/VK1-5 antibodies. Serologic testing shows that antibodies to this region correlate with serum neutralizing activity to ZIKV. Thus, high neutralizing responses to ZIKV are associated with pre-existing reactivity to DENV1 in humans.
      Graphical abstract image Teaser Individuals with high neutralizing antibody response against Zika virus have expanded clones of B cells that express the same heavy and light immunoglobulin genes and that are cross-reactive against dengue 1 virus.

      PubDate: 2017-05-07T12:12:57Z
       
  • Regulation of Cerebral Cortex Folding by Controlling Neuronal Migration
           via FLRT Adhesion Molecules
    • Abstract: Publication date: 4 May 2017
      Source:Cell, Volume 169, Issue 4
      Author(s): Daniel del Toro, Tobias Ruff, Erik Cederfjäll, Ana Villalba, Gönül Seyit-Bremer, Víctor Borrell, Rüdiger Klein
      The folding of the mammalian cerebral cortex into sulci and gyri is thought to be favored by the amplification of basal progenitor cells and their tangential migration. Here, we provide a molecular mechanism for the role of migration in this process by showing that changes in intercellular adhesion of migrating cortical neurons result in cortical folding. Mice with deletions of FLRT1 and FLRT3 adhesion molecules develop macroscopic sulci with preserved layered organization and radial glial morphology. Cortex folding in these mutants does not require progenitor cell amplification but is dependent on changes in neuron migration. Analyses and simulations suggest that sulcus formation in the absence of FLRT1/3 results from reduced intercellular adhesion, increased neuron migration, and clustering in the cortical plate. Notably, FLRT1/3 expression is low in the human cortex and in future sulcus areas of ferrets, suggesting that intercellular adhesion is a key regulator of cortical folding across species.
      Graphical abstract image Teaser Physical migration of neurons can create the folded cortical surface characteristic of primate brains.

      PubDate: 2017-05-07T12:12:57Z
       
  • Diurnal Oscillations in Liver Mass and Cell Size Accompany Ribosome
           Assembly Cycles
    • Abstract: Publication date: 4 May 2017
      Source:Cell, Volume 169, Issue 4
      Author(s): Flore Sinturel, Alan Gerber, Daniel Mauvoisin, Jingkui Wang, David Gatfield, Jeremy J. Stubblefield, Carla B. Green, Frédéric Gachon, Ueli Schibler
      The liver plays a pivotal role in metabolism and xenobiotic detoxification, processes that must be particularly efficient when animals are active and feed. A major question is how the liver adapts to these diurnal changes in physiology. Here, we show that, in mice, liver mass, hepatocyte size, and protein levels follow a daily rhythm, whose amplitude depends on both feeding-fasting and light-dark cycles. Correlative evidence suggests that the daily oscillation in global protein accumulation depends on a similar fluctuation in ribosome number. Whereas rRNA genes are transcribed at similar rates throughout the day, some newly synthesized rRNAs are polyadenylated and degraded in the nucleus in a robustly diurnal fashion with a phase opposite to that of ribosomal protein synthesis. Based on studies with cultured fibroblasts, we propose that rRNAs not packaged into complete ribosomal subunits are polyadenylated by the poly(A) polymerase PAPD5 and degraded by the nuclear exosome.
      Graphical abstract image Teaser Daily oscillations in liver size arise from regulated changes in the number and activity of ribosomes.

      PubDate: 2017-05-07T12:12:57Z
       
  • SLERT Regulates DDX21 Rings Associated with Pol I Transcription
    • Abstract: Publication date: 4 May 2017
      Source:Cell, Volume 169, Issue 4
      Author(s): Yu-Hang Xing, Run-Wen Yao, Yang Zhang, Chun-Jie Guo, Shan Jiang, Guang Xu, Rui Dong, Li Yang, Ling-Ling Chen
      Dysregulated rRNA synthesis by RNA polymerase I (Pol I) is associated with uncontrolled cell proliferation. Here, we report a box H/ACA small nucleolar RNA (snoRNA)-ended long noncoding RNA (lncRNA) that enhances pre-rRNA transcription (SLERT). SLERT requires box H/ACA snoRNAs at both ends for its biogenesis and translocation to the nucleolus. Deletion of SLERT impairs pre-rRNA transcription and rRNA production, leading to decreased tumorigenesis. Mechanistically, SLERT interacts with DEAD-box RNA helicase DDX21 via a 143-nt non-snoRNA sequence. Super-resolution images reveal that DDX21 forms ring-shaped structures surrounding multiple Pol I complexes and suppresses pre-rRNA transcription. Binding by SLERT allosterically alters individual DDX21 molecules, loosens the DDX21 ring, and evicts DDX21 suppression on Pol I transcription. Together, our results reveal an important control of ribosome biogenesis by SLERT lncRNA and its regulatory role in DDX21 ring-shaped arrangements acting on Pol I complexes.
      Graphical abstract image Teaser A long non-coding RNA promotes pre-ribosomal RNA transcription by loosening the ring-shaped structure surrounding multiple RNA Pol I complexes formed by RNA helicase DDX21.

      PubDate: 2017-05-07T12:12:57Z
       
  • The RNA Exosome Syncs IAV-RNAPII Transcription to Promote Viral
           Ribogenesis and Infectivity
    • Abstract: Publication date: 4 May 2017
      Source:Cell, Volume 169, Issue 4
      Author(s): Alexander Rialdi, Judd Hultquist, David Jimenez-Morales, Zuleyma Peralta, Laura Campisi, Romain Fenouil, Natasha Moshkina, Zhen Zhen Wang, Brice Laffleur, Robyn M. Kaake, Michael J. McGregor, Kelsey Haas, Evangelos Pefanis, Randy A. Albrecht, Lars Pache, Sumit Chanda, Joanna Jen, Jordi Ochando, Minji Byun, Uttiya Basu, Adolfo García-Sastre, Nevan Krogan, Harm van Bakel, Ivan Marazzi
      The nuclear RNA exosome is an essential multi-subunit complex that controls RNA homeostasis. Congenital mutations in RNA exosome genes are associated with neurodegenerative diseases. Little is known about the role of the RNA exosome in the cellular response to pathogens. Here, using NGS and human and mouse genetics, we show that influenza A virus (IAV) ribogenesis and growth are suppressed by impaired RNA exosome activity. Mechanistically, the nuclear RNA exosome coordinates the initial steps of viral transcription with RNAPII at host promoters. The viral polymerase complex co-opts the nuclear RNA exosome complex and cellular RNAs en route to 3′ end degradation. Exosome deficiency uncouples chromatin targeting of the viral polymerase complex and the formation of cellular:viral RNA hybrids, which are essential RNA intermediates that license transcription of antisense genomic viral RNAs. Our results suggest that evolutionary arms races have shaped the cellular RNA quality control machinery.
      Graphical abstract image Teaser The RNA exosome is critical for influenza virus ribogenesis and infectivity, working as a platform that coordinates the activity of viral and cellular RNA polymerases.

      PubDate: 2017-05-07T12:12:57Z
       
  • The Cohesin Release Factor WAPL Restricts Chromatin Loop Extension
    • Abstract: Publication date: 4 May 2017
      Source:Cell, Volume 169, Issue 4
      Author(s): Judith H.I. Haarhuis, Robin H. van der Weide, Vincent A. Blomen, J. Omar Yáñez-Cuna, Mario Amendola, Marjon S. van Ruiten, Peter H.L. Krijger, Hans Teunissen, René H. Medema, Bas van Steensel, Thijn R. Brummelkamp, Elzo de Wit, Benjamin D. Rowland
      The spatial organization of chromosomes influences many nuclear processes including gene expression. The cohesin complex shapes the 3D genome by looping together CTCF sites along chromosomes. We show here that chromatin loop size can be increased and that the duration with which cohesin embraces DNA determines the degree to which loops are enlarged. Cohesin’s DNA release factor WAPL restricts this loop extension and also prevents looping between incorrectly oriented CTCF sites. We reveal that the SCC2/SCC4 complex promotes the extension of chromatin loops and the formation of topologically associated domains (TADs). Our data support the model that cohesin structures chromosomes through the processive enlargement of loops and that TADs reflect polyclonal collections of loops in the making. Finally, we find that whereas cohesin promotes chromosomal looping, it rather limits nuclear compartmentalization. We conclude that the balanced activity of SCC2/SCC4 and WAPL enables cohesin to correctly structure chromosomes.
      Graphical abstract image Teaser Cohesin's dynamic association with DNA determines the length of chromatin loops and allows this complex to correctly structure chromosomes.

      PubDate: 2017-05-07T12:12:57Z
       
  • Molecular Mechanism of Substrate Processing by the Cdc48 ATPase Complex
    • Abstract: Publication date: 4 May 2017
      Source:Cell, Volume 169, Issue 4
      Author(s): Nicholas O. Bodnar, Tom A. Rapoport
      The Cdc48 ATPase and its cofactors Ufd1/Npl4 (UN) extract polyubiquitinated proteins from membranes or macromolecular complexes, but how they perform these functions is unclear. Cdc48 consists of an N-terminal domain that binds UN and two stacked hexameric ATPase rings (D1 and D2) surrounding a central pore. Here, we use purified components to elucidate how the Cdc48 complex processes substrates. After interaction of the polyubiquitin chain with UN, ATP hydrolysis by the D2 ring moves the polypeptide completely through the double ring, generating a pulling force on the substrate and causing its unfolding. ATP hydrolysis by the D1 ring is important for subsequent substrate release from the Cdc48 complex. This release requires cooperation of Cdc48 with a deubiquitinase, which trims polyubiquitin to an oligoubiquitin chain that is then also translocated through the pore. Together, these results lead to a new paradigm for the function of Cdc48 and its mammalian ortholog p97/VCP.
      Graphical abstract image Teaser Polyubiquitinated, misfolded substrates are extracted from membranes and macromolecular complexes by Cdc48 and its cofactors via a pulling force that causes substrate unfolding and are then released by the trimming of polyubiquitin chains to oligoubiquitin.

      PubDate: 2017-05-07T12:12:57Z
       
  • An Immune Atlas of Clear Cell Renal Cell Carcinoma
    • Abstract: Publication date: 4 May 2017
      Source:Cell, Volume 169, Issue 4
      Author(s): Stéphane Chevrier, Jacob Harrison Levine, Vito Riccardo Tomaso Zanotelli, Karina Silina, Daniel Schulz, Marina Bacac, Carola Hermine Ries, Laurie Ailles, Michael Alexander Spencer Jewett, Holger Moch, Maries van den Broek, Christian Beisel, Michael Beda Stadler, Craig Gedye, Bernhard Reis, Dana Pe’er, Bernd Bodenmiller
      Immune cells in the tumor microenvironment modulate cancer progression and are attractive therapeutic targets. Macrophages and T cells are key components of the microenvironment, yet their phenotypes and relationships in this ecosystem and to clinical outcomes are ill defined. We used mass cytometry with extensive antibody panels to perform in-depth immune profiling of samples from 73 clear cell renal cell carcinoma (ccRCC) patients and five healthy controls. In 3.5 million measured cells, we identified 17 tumor-associated macrophage phenotypes, 22 T cell phenotypes, and a distinct immune composition correlated with progression-free survival, thereby presenting an in-depth human atlas of the immune tumor microenvironment in this disease. This study revealed potential biomarkers and targets for immunotherapy development and validated tools that can be used for immune profiling of other tumor types.
      Graphical abstract image Teaser Applying mass cytometry for high-dimensional single-cell analysis depicts an in-depth atlas of the immune microenvironment in clear cell renal cell carcinoma patients, thereby linking immune compositions with clinical features.

      PubDate: 2017-05-07T12:12:57Z
       
  • Innate Immune Landscape in Early Lung Adenocarcinoma by Paired Single-Cell
           Analyses
    • Abstract: Publication date: 4 May 2017
      Source:Cell, Volume 169, Issue 4
      Author(s): Yonit Lavin, Soma Kobayashi, Andrew Leader, El-ad David Amir, Naama Elefant, Camille Bigenwald, Romain Remark, Robert Sweeney, Christian D. Becker, Jacob H. Levine, Klaus Meinhof, Andrew Chow, Seunghee Kim-Shulze, Andrea Wolf, Chiara Medaglia, Hanjie Li, Julie A. Rytlewski, Ryan O. Emerson, Alexander Solovyov, Benjamin D. Greenbaum, Catherine Sanders, Marissa Vignali, Mary Beth Beasley, Raja Flores, Sacha Gnjatic, Dana Pe’er, Adeeb Rahman, Ido Amit, Miriam Merad
      To guide the design of immunotherapy strategies for patients with early stage lung tumors, we developed a multiscale immune profiling strategy to map the immune landscape of early lung adenocarcinoma lesions to search for tumor-driven immune changes. Utilizing a barcoding method that allows a simultaneous single-cell analysis of the tumor, non-involved lung, and blood cells, we provide a detailed immune cell atlas of early lung tumors. We show that stage I lung adenocarcinoma lesions already harbor significantly altered T cell and NK cell compartments. Moreover, we identified changes in tumor-infiltrating myeloid cell (TIM) subsets that likely compromise anti-tumor T cell immunity. Paired single-cell analyses thus offer valuable knowledge of tumor-driven immune changes, providing a powerful tool for the rational design of immune therapies. Video
      Graphical abstract image Teaser Comparing single tumor cells with adjacent normal tissue and blood from patients with lung adenocarcinoma charts early changes in tumor immunity and provides insights to guide immunotherapy design.

      PubDate: 2017-05-07T12:12:57Z
       
  • SnapShot:Macropinocytosis
    • Abstract: Publication date: 4 May 2017
      Source:Cell, Volume 169, Issue 4
      Author(s): Pedro E. Marques, Sergio Grinstein, Spencer A. Freeman
      Macropinocytosis is the bulk ingestion of extracellular fluids via large endocytic vacuoles. This SnapShot provides an overview of physiological macropinocytosis in immune surveillance and its pathogenic contribution during infection and cancer proliferation.
      Teaser Macropinocytosis is the bulk ingestion of extracellular fluids via large endocytic vacuoles. This SnapShot provides an overview of physiological macropinocytosis in immune surveillance and its pathogenic contribution during infection and cancer proliferation.

      PubDate: 2017-05-07T12:12:57Z
       
  • 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
       
  • Zika Virus Persistence in the Central Nervous System and Lymph Nodes of
           Rhesus Monkeys
    • Abstract: Publication date: Available online 27 April 2017
      Source:Cell
      Author(s): Malika Aid, Peter Abbink, Rafael A. Larocca, Michael Boyd, Ramya Nityanandam, Ovini Nanayakkara, Amanda J. Martinot, Edward T. Moseley, Eryn Blass, Erica N. Borducchi, Abishek Chandrashekar, Amanda L. Brinkman, Katherine Molloy, David Jetton, Lawrence J. Tartaglia, Jinyan Liu, Katharine Best, Alan S. Perelson, Rafael A. De La Barrera, Mark G. Lewis, Dan H. Barouch
      Zika virus (ZIKV) is associated with severe neuropathology in neonates as well as Guillain-Barré syndrome and other neurologic disorders in adults. Prolonged viral shedding has been reported in semen, suggesting the presence of anatomic viral reservoirs. Here we show that ZIKV can persist in cerebrospinal fluid (CSF) and lymph nodes (LN) of infected rhesus monkeys for weeks after virus has been cleared from peripheral blood, urine, and mucosal secretions. ZIKV-specific neutralizing antibodies correlated with rapid clearance of virus in peripheral blood but remained undetectable in CSF for the duration of the study. Viral persistence in both CSF and LN correlated with upregulation of mechanistic target of rapamycin (mTOR), proinflammatory, and anti-apoptotic signaling pathways, as well as downregulation of extracellular matrix signaling pathways. These data raise the possibility that persistent or occult neurologic and lymphoid disease may occur following clearance of peripheral virus in ZIKV-infected individuals.
      Graphical abstract image Teaser Persistence of Zika virus in the CNS and lymphoid tissues of NHPs suggests that ZIKV infection may have consequences to humans beyond the reported birth defects.

      PubDate: 2017-05-01T06:06:09Z
       
  • Cryo-EM Structure of a Relaxase Reveals the Molecular Basis of DNA
           Unwinding during Bacterial Conjugation
    • Abstract: Publication date: Available online 27 April 2017
      Source:Cell
      Author(s): Aravindan Ilangovan, Christopher W.M. Kay, Sandro Roier, Hassane El Mkami, Enrico Salvadori, Ellen L. Zechner, Giulia Zanetti, Gabriel Waksman
      Relaxases play essential roles in conjugation, the main process by which bacteria exchange genetic material, notably antibiotic resistance genes. They are bifunctional enzymes containing a trans-esterase activity, which is responsible for nicking the DNA strand to be transferred and for covalent attachment to the resulting 5′-phosphate end, and a helicase activity, which is responsible for unwinding the DNA while it is being transported to a recipient cell. Here we show that these two activities are carried out by two conformers that can both load simultaneously on the origin of transfer DNA. We solve the structure of one of these conformers by cryo electron microscopy to near-atomic resolution, elucidating the molecular basis of helicase function by relaxases and revealing insights into the mechanistic events taking place in the cell prior to substrate transport during conjugation.
      Graphical abstract image Teaser To achieve genetic exchange during bacterial conjugation, two relaxase monomers collaborate, adopting distinct structural conformations to provide the two necessary enzymatic activities for processing the DNA.

      PubDate: 2017-05-01T06:06:09Z
       
  • Bringing Culture to Bacteria
    • Abstract: Publication date: 20 April 2017
      Source:Cell, Volume 169, Issue 3
      Author(s): Mirna Kvajo


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

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

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

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

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

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

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

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

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

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

      PubDate: 2017-04-24T05:00:52Z
       
 
 
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