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[Science] 31 MAY 2013 VOL 340, ISSUE 6136, PAGES 1005-1132 EDITORIAL: After 5 Years at Science Bruce Alberts Science 31 May 2013: 1015. Podcast Interview Perspectives-CELL BIOLOGY Vitamin Currency in a Lipid Exchange Market Bruno Mesmin and Bruno Antonny Science 31 May 2013: 1051-1052. A lipid transfer protein moves vitamin E through the cell to the cell surface by exchanging it for a phosphoinositide in the plasma membrane. Science. 2013 May 31;340(6136):1106-10. doi: 10.1126/science.1233508. Epub 2013 Apr 18. Impaired α-TTP-PIPs interaction underlies familial vitamin E deficiency. Kono N, Ohto U, Hiramatsu T, Urabe M, Uchida Y, Satow Y, Arai H. Graduate School of Pharmaceutical Sciences, University of Tokyo, Tokyo, Japan. α-Tocopherol (vitamin E) transfer protein (α-TTP) regulates the secretion of α-tocopherol from liver cells. Missense mutations of some arginine residues at the surface of α-TTP cause severe vitamin E deficiency in humans, but the role of these residues is unclear. Here, we found that wild-type α-TTP bound phosphatidylinositol phosphates (PIPs), whereas the arginine mutants did not. In addition, PIPs in the target membrane promoted the intermembrane transfer of α-tocopherol by α-TTP. The crystal structure of the α-TTP-PIPs complex revealed that the disease-related arginine residues interacted with phosphate groups of the PIPs and that the PIPs binding caused the lid of the α-tocopherol-binding pocket to open. Thus, PIPs have a role in promoting the release of a ligand from a lipid-transfer protein. [Science] 31 MAY 2013 VOL 340, ISSUE 6136, PAGES 1005-1132 Perspectives - CELL BIOLOGY GATORs Take a Bite Out of mTOR Reuben J. Shaw Science 31 May 2013: 1056-1057. A negative regulator of amino acid sensing by the mTOR signaling pathway is identified and discovered to be inactivated in cancers. Science. 2013 May 31;340(6136):1100-6. doi: 10.1126/science.1232044. A Tumor suppressor complex with GAP activity for the Rag GTPases that signal amino acid sufficiency tomTORC1. Bar-Peled L, Chantranupong L, Cherniack AD, Chen WW, Ottina KA, Grabiner BC, Spear ED, Carter SL, Meyerson M, Sabatini DM. Whitehead Institute for Biomedical Research and Massachusetts Institute of Technology, Department of Biology, Cambridge, MA 02142, USA. The mTOR complex 1 (mTORC1) pathway promotes cell growth in response to many cues, including amino acids, which act through the Ragguanosine triphosphatases (GTPases) to promote mTORC1 translocation to the lysosomal surface, its site of activation. Although progress has been made in identifying positive regulators of the Rags, it is unknown if negative factors also exist. Here, we identify GATOR as a complex that interacts with the Rags and is composed of two subcomplexes we call GATOR1 and -2. Inhibition of GATOR1 subunits (DEPDC5, Nprl2, and Nprl3) makes mTORC1 signaling resistant to amino acid deprivation. In contrast, inhibition of GATOR2 subunits (Mios, WDR24, WDR59, Seh1L, and Sec13) suppresses mTORC1 signaling, and epistasis analysis shows that GATOR2 negatively regulates DEPDC5. GATOR1 has GTPase-activating protein (GAP) activity for RagA and RagB, and its components are mutated in human cancer. In cancer cells with inactivating mutations in GATOR1, mTORC1 is hyperactive and insensitive to amino acid starvation, and such cells are hypersensitive to rapamycin, an mTORC1inhibitor. Thus, we identify a key negative regulator of the Rag GTPases and reveal that, like other mTORC1 regulators, Rag function can be deregulated in cancer [Science] 31 MAY 2013 VOL 340, ISSUE 6136, PAGES 1005-1132 A Conserved Mechanism for Centromeric Nucleosome Recognition by Centromere Protein CENP-C Hidenori Kato, Jiansheng Jiang, Bing-Rui Zhou, Marieke Rozendaal, Hanqiao Feng, Rodolfo Ghirlando, T. Sam Xiao, Aaron F. Straight, and Yawen Bai Science 31 May 2013: 1110-1113. The structural links between the chromosomal centromere protein CenH3 and the kinetochore protein CENP-C are determined. Structure of RSV Fusion Glycoprotein Trimer Bound to a Prefusion-Specific Neutralizing Antibody Jason S. McLellan, Man Chen, Sherman Leung, Kevin W. Graepel, Xiulian Du, Yongping Yang, Tongqing Zhou, Ulrich Baxa,Etsuko Yasuda, Tim Beaumont, Azad Kumar, Kayvon Modjarrad, Zizheng Zheng, Min Zhao, Ningshao Xia, Peter D. Kwong,and Barney S. Graham Science 31 May 2013: 1113-1117. The prefusion conformation of respiratory syncytial virus protein F has been trapped by a neutralizing antibody. Tracking Individuals Shows Spatial Fidelity Is a Key Regulator of Ant Social Organization Danielle P. Mersch, Alessandro Crespi, and Laurent Keller Science 31 May 2013: 1090-1093. Monitoring of individually tagged worker ants revealed three distinct groups that greatly differ in behavior. Mechanisms of Age-Dependent Response to Winter Temperature in Perennial Flowering of Arabis alpina Sara Bergonzi, Maria C. Albani, Emiel Ver Loren van Themaat, Karl J. V. Nordström, Renhou Wang, Korbinian Schneeberger, Perry D. Moerland, and George Coupland Science 31 May 2013: 1094-1097. MicroRNAs regulate perennial flowering. Molecular Basis of Age-Dependent Vernalization in Cardamine flexuosa Chuan-Miao Zhou, Tian-Qi Zhang, Xi Wang, Sha Yu, Heng Lian, Hongbo Tang, Zheng-Yan Feng, Judita Zozomova-Lihová, and Jia-Wei Wang Science 31 May 2013: 1097-1100. MicroRNAs regulate perennial flowering. [Science Sig] 28 MAY 2013 VOL 6, ISSUE 277 [Science Trans Med] 29 MAY 2013 VOL 5, ISSUE 187 Sci Transl Med. 2013 May 29;5(187):187ra71. doi: 10.1126/scitranslmed.3005688. A preclinical xenograft model identifies castration-tolerant cancer-repopulating cells in localized prostatetumors. Toivanen R, Frydenberg M, Murphy D, Pedersen J, Ryan A, Pook D, Berman DM; Australian Prostate Cancer BioResource, Taylor RA, Risbridger GP. Department of Anatomy and Developmental Biology, Monash University, Clayton, Victoria 3800, Australia. A lack of clinically relevant experimental models of human prostate cancer hampers evaluation of potential therapeutic agents. Currently, androgen deprivation therapy is the gold standard treatment for advanced prostate cancer, but inevitably, a subpopulation of cancer cellssurvives and repopulates the tumor. Tumor cells that survive androgen withdrawal are critical therapeutic targets for more effective treatments, but current model systems cannot determine when they arise in disease progression and are unable to recapitulate variable patient response to treatment. A model system was developed in which stromal-supported xenografts from multiple patients with early-stage localized disease can be tested for response to castration. The histopathology of these xenografts mimicked the original tumors, and short-term host castration resulted in reduced proliferation and increased apoptosis in tumor cells. After 4 weeks of castration, residual populations of quiescent, stem-like tumor cellsremained. Without subsequent treatment, these residual cells displayed regenerative potential, because testosterone readministration resulted in emergence of rapidly proliferating tumors. Therefore, this model may be useful for revealing potential cellular targets in prostate cancer, which exist before the onset of aggressive incurable disease. Specific eradication of these regenerative tumor cells that survive castration could then confer survival benefits for patients. DRUG TOXICITY Coronary Microvascular Pericytes Are the Cellular Target of Sunitinib Malate–Induced Cardiotoxicity Vishnu Chintalgattu, Meredith L. Rees, James C. Culver, Aditya Goel, Tilahu Jiffar, Jianhu Zhang, Kenneth Dunner, Jr., Shibani Pati,James A. Bankson, Renata Pasqualini, Wadih Arap, Nathan S. Bryan, Heinrich Taegtmeyer, Robert R. Langley, Hui Yao,Michael E. Kupferman, Mark L. Entman, Mary E. Dickinson, and Aarif Y. Khakoo Sunitinib-induced cardiotoxicity is caused by depletion of coronary pericytes due to loss of PDGFR signaling; this side effect can be prevented by thalidomide. KJ Wnt Signaling Regulates the Lineage Differentiation Potential of Mouse Embryonic Stem Cells through Tcf3 Down-Regulation Yaser Atlasi, X Rubina Noori, X Claudia Gaspar, X Patrick Franken, X Andrea Sacchetti, X Haleh Rafati, X Tokameh Mahmoudi, X Charles Decraene, X George A. Calin, X Bradley J. Merrill, X Riccardo Fodde Abstract Canonical Wnt signaling plays a rate-limiting role in regulating self-renewal and differentiation in mouse embryonic stem cells (ESCs). We have previously shown that mutation in the Apc (adenomatous polyposis coli) tumor suppressor gene constitutively activates Wnt signaling in ESCs and inhibits their capacity to differentiate towards ecto-, meso-, and endodermal lineages. However, the underlying molecular and cellular mechanisms through which Wnt regulates lineage differentiation in mouse ESCs remain to date largely unknown. To this aim, we have derived and studied the gene expression profiles of several Apc-mutant ESC lines encoding for different levels of Wnt signaling activation. We found that down-regulation of Tcf3, a member of the Tcf/Lef family and a key player in the control of self-renewal and pluripotency, represents a specific and primary response to Wnt activation in ESCs. Accordingly, rescuing Tcf3 expression partially restored the neural defects observed in Apc-mutant ESCs, suggesting that Tcf3 down-regulation is a necessary step towards Wnt-mediated suppression of neural differentiation. We found that Tcf3 downregulation in the context of constitutively active Wnt signaling does not result from promoter DNA methylation but is likely to be caused by a plethora of mechanisms at both the RNA and protein level as shown by the observed decrease in activating histone marks (H3K4me3 and H3-acetylation) and the upregulation of miR-211, a novel Wnt-regulated microRNA that targets Tcf3 and attenuates early neural differentiation in mouse ESCs. Our data show for the first time that Wnt signaling down-regulates Tcf3 expression, possibly at both the transcriptional and post-transcriptional levels, and thus highlight a novel mechanism through which Wnt signaling inhibits neuro-ectodermal lineage differentiation in mouse embryonic stem cells. KJ KJ KJ Developmental Immunology and Center for Computational and Integrative Biology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA. Phagocytosis is a fundamental cellular process that is pivotal for immunity as it coordinates microbial killing, innate immune activation and antigen presentation. An essential step in this process is phagosome acidification, which regulates many functions of these organelles that allow phagosomes to participate in processes that are essential to both innate and adaptive immunity. Here we report that acidification of phagosomes containing Gram-positive bacteria is regulated by the NLRP3 inflammasome and caspase-1. Active caspase-1 accumulates on phagosomes and acts locally to control the pH by modulating buffering by the NADPH oxidase NOX2. These data provide insight into a mechanism by which innate immune signals can modify cellular defenses and establish a new function for the NLRP3 inflammasome and caspase-1 in host defense. Wnt Signaling Regulates the Lineage Differentiation Potential of Mouse Embryonic Stem Cells through Tcf3 Down-Regulation Yaser Atlasi1, Rubina Noori1, Claudia Gaspar1¤, Patrick Franken1, Andrea Sacchetti1, Haleh Rafati2, Tokameh Mahmoudi2, Charles Decraene3,4, George A. Calin5, Bradley J. Merrill6, Riccardo Fodde1* 1 Department of Pathology, Josephine Nefkens Institute, Erasmus MC, Rotterdam, The Netherlands, 2 Department of Biochemistry, Erasmus MC, Rotterdam, The Netherlands, 3 Translational Research Department, Institut Curie, Centre de Recherche, Paris, France, 4 CNRS, UMR144, Paris, France, 5 Department of Experimental Therapeutics and Center for RNA Interference and Non-Coding RNAs, MD Anderson Cancer Center, Houston, Texas, United States of America, 6 Department of Biochemistry and Molecular Genetics, University of Illinois, Chicago, Illinois, United States of America Abstract Canonical Wnt signaling plays a rate-limiting role in regulating self-renewal and differentiation in mouse embryonic ste m cells (ESCs). We have previously shown that mutation in the Apc (adenomatous polyposis coli) tumor suppressor gen e constitutively activates Wnt signaling in ESCs and inhibits their capacity to differentiate towards ecto-, meso-, and end odermal lineages. However, the underlying molecular and cellular mechanisms through which Wnt regulates lineage dif ferentiation in mouse ESCs remain to date largely unknown. To this aim, we have derived and studied the gene expressi on profiles of several Apc-mutant ESC lines encoding for different levels of Wnt signaling activation. We found that dow n-regulation of Tcf3, a member of the Tcf/Lef family and a key player in the control of self-renewal and pluripotency, re presents a specific and primary response to Wnt activation in ESCs. Accordingly, rescuing Tcf3 expression partially restor ed the neural defects observed in Apc-mutant ESCs, suggesting that Tcf3 down-regulation is a necessary step towards Wnt-mediated suppression of neural differentiation. We found that Tcf3 down-regulation in the context of constitutivel y active Wnt signaling does not result from promoter DNA methylation but is likely to be caused by a plethora of mech anisms at both the RNA and protein level as shown by the observed decrease in activating histone marks (H3K4me3 an d H3-acetylation) and the upregulation of miR-211, a novel Wnt-regulated microRNA that targets Tcf3 and attenuates e arly neural differentiation in mouse ESCs. Our data show for the first time that Wnt signaling down-regulates Tcf3 expre ssion, possibly at both the transcriptional and post-transcriptional levels, and thus highlight a novel mechanism through which Wnt signaling inhibits neuro-ectodermal lineage differentiation in mouse embryonic stem cells. Interactions with Iridophores and the Tissue Environment Required f or Patterning Melanophores and Xanthophores during Zebrafish Adu lt Pigment Stripe Formation Larissa B. Patterson, David M. Parichy CDK4 T172 Phosphorylation Is Central in a CDK7-Dependent Bidirect ional CDK4/CDK2 Interplay Mediated by p21 Phosphorylation at the Restriction Point Xavier Bisteau, Sabine Paternot, Bianca Colleoni, K arin Ecker, Katia Coulonval, Philippe De Groote, Wim Declercq, Ludg er Hengst, Pierre P. Roger DNA Binding of the Cell Cycle Transcriptional Regulator GcrA Depen ds on N6-Adenosine Methylation in Caulobacter crescentus and Othe r Alphaproteobacteria Antonella Fioravanti, Coralie Fumeaux, Saswat S. Mohapatra, Coralie Bompard, Matteo Brilli, Antonio Frandi, Vincent Castric, Vincent Ville ret, Patrick H. Viollier, Emanuele G. Biondi Cell Polarity and Patterning by PIN Trafficking through Early Endoso mal Compartments in Arabidopsis thaliana Hirokazu Tanaka, Saeko Kitakura, Hana Rakusová, Tomohiro Uemura , Mugurel I. Feraru, Riet De Rycke, Stéphanie Robert, Tatsuo Kakimot o, Jiří Friml GLIS3, a Susceptibility Gene for Type 1 and Type 2 Diabetes, Modulat es Pancreatic Beta Cell Apoptosis via Regulation of a Splice Variant of the BH3-Only Protein Bim Tatiane C. Nogueira, Flavia M. Paula, Ol atz Villate, Maikel L. Colli, Rodrigo F. Moura, Daniel A. Cunha, Lorella Marselli, Piero Marchetti, Miriam Cnop, Cécile Julier, Decio L. Eizirik Side Effects: Substantial Non-Neutral Evolution Flanking Regulatory Sites James G. D. Prendergast, Colin A. Strong Purifying Selection at Synonymous Sites in D. melan ogaster David S. Lawrie, Philipp W. Messer, Ruth Hershberg, Dmitri A. Petrov Using Extended Genealogy to Estimate Components of Herit ability for 23 Quantitative and Dichotomous Traits Noah Zaitlen, Peter Kraft, Nick Patterson, Bogdan Pasaniuc, Gaurav Bhatia, Samuela Pollack, Alkes L. Price Drosophila Functional Elements Are Embedded in Structural ly Constrained Sequences Ephraim Kenigsberg, Amos Tanay Global Properties and Functional Complexity of Human Gen e Regulatory Variation Daniel J. Gaffney From Paramutation to Paradigm Ian R. Adams, Richard R. Meehan Arabidopsis thaliana RESISTANCE TO FUSARIUM OXYSPO RUM 2 Implicates Tyrosine-Sulfated Peptide Signaling in Su sceptibility and Resistance to Root Infection Yunping Shen, Andrew C. Diener ttm-1 Encodes CDF Transporters That Excrete Zinc from Inte stinal Cells of C. elegans and Act in a Parallel Negative Feed back Circuit That Promotes Homeostasis Hyun Cheol Roh, Sara Collier, Krupa Deshmukh, James Gut hrie, J. David Robertson, Kerry Kornfeld Ikbkap/Elp1 Deficiency Causes Male Infertility by Disrupting Meiotic Progression Fu-Jung Lin, Li Shen, Chuan-Wei Jang, Pål Ø. Falnes, Yi Zhang RNA–Mediated Epigenetic Heredity Requires the Cytosine Methyltra nsferase Dnmt2 Jafar Kiani, Valérie Grandjean, Reinhard Liebers, Francesca Tuorto, Hossein Ghanbarian, Frank Lyko, François Cuzin, Minoo Rassoulzade gan Analysis of the Genetic Basis of Disease in the Context of Worldwid e Human Relationships and Migration Erik Corona, Rong Chen, Mar tin Sikora, Alexander A. Morgan, Chirag J. Patel, Aditya Ramesh, Ca rlos D. Bustamante, Atul J. Butte Clathrin and AP2 Are Required for Phagocytic Receptor-Mediated A poptotic Cell Clearance in Caenorhabditis elegans Didi Chen, Youli J ian, Xuezhao Liu, Yuanya Zhang, Jingjing Liang, Xiaying Qi, Hongwe i Du, Wei Zou, Lianwan Chen, Yongping Chai, Guangshuo Ou, Long Miao, Yingchun Wang, Chonglin Yang The Secretory Pathway Calcium ATPase PMR-1/SPCA1 Has Essential Roles in Cell Migration during Caenorhabditis elegans Embryonic D evelopment Vida Praitis, Jeffrey Simske, Sarah Kniss, Rebecca Mandt, Leah Imlay , Charlotte Feddersen, Michael B. Miller, Juliet Mushi, Walter Liszew ski, Rachel Weinstein, Adityarup Chakravorty, Dae-Gon Ha, Angela Schacht Farrell, Alexander Sullivan-Wilson, Tyson Stock ATM–Dependent MiR-335 Targets CtIP and Modulates the DNA Da mage Response Nathan T. Martin, Kotoka Nakamura, Robert Davies, Shareef A. Nah as, Christina Brown, Rashmi Tunuguntla, Richard A. Gatti, Hailiang Hu HDAC7 Is a Repressor of Myeloid Genes Whose Downregul ation Is Required for Transdifferentiation of Pre-B Cells int o Macrophages Bruna Barneda-Zahonero, Lidia Román-González, Olga Colla zo, Haleh Rafati, Abul B. M. M. K. Islam, Lars H. Bussmann, Alessandro di Tullio, Luisa De Andres, Thomas Graf, Núria L ópez-Bigas, Tokameh Mahmoudi, Maribel Parra Human Genetics in Rheumatoid Arthritis Guides a High-Thr oughput Drug Screen of the CD40 Signaling Pathway Gang Li, Dorothée Diogo, Di Wu…………………Robert M. Ple nge Liver X Receptors Protect from Development of Prostatic In tra-Epithelial Neoplasia in Mice Aurélien J. C. Pommier, Juli e Dufour, Georges Alves, Emilie Viennois, Hugues De Bouss ac, Amalia Trousson, David H. Volle, Françoise Caira, Pierre Val, Philippe Arnaud, Jean-Marc A. Lobaccaro, Silvère Baron Genome-Wide Analysis in German Shepherd Dogs Reveals Association of a Locus on CFA 27 with Atopic Dermatitis Ka tarina Tengvall, Marcin Kierczak, Kerstin Bergvall, Mia Olsso n, Marcel Frankowiack, Fabiana H. G. Farias, Gerli Pielberg, Örjan Carlborg, Tosso Leeb, Göran Andersson, Lennart Ham marström, Åke Hedhammar, Kerstin Lindblad-Toh Wnt Signaling Regulates the Lineage Differentiation Potenti al of Mouse Embryonic Stem Cells through Tcf3 Down-Reg ulation Yaser Atlasi, Rubina Noori, Claudia Gaspar, Patrick F ranken, Andrea Sacchetti, Haleh Rafati, Tokameh Mahmoud i, Charles Decraene, George A. Calin, Bradley J. Merrill, Ricc ardo Fodde Research Article | published 02 May 2013 | PLO S Genetics