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[Science] 10 May 2013 vol 340, issue 6133, pages 653-776 Perspectives - Immunology Crowdsourcing Immunity James E. Crowe Jr. Science 10 May 2013: 692-693.[DOI:10.1126/science.1238628] Computational methods reveal the nature and diversity of antibodies in HIV-infected individuals. Reports Delineating Antibody Recognition in Polyclonal Sera from Patterns of HIV-1 Isolate Neutralization Ivelin S. Georgiev, Nicole A. Doria-Rose, Tongqing Zhou, Young Do Kwon, Ryan P. Staupe, Stephanie Moquin, Gwo-Yu Chuang, Mark K. Louder, Stephen D. Schmidt, Han R. Altae-Tran, Robert T. Bailer, Krisha McKee, Martha Nason, Sijy O’Dell, Gilad Ofek, Marie Pancera, Sanjay Srivatsan, Lawrence Shapiro, Mark Connors, Stephen A. Migueles, Lynn Morris, Yoshiaki Nishimura, Malcolm A. Martin, John R. Mascola, and Peter D. Kwong Science 10 May 2013: 751-756.[DOI:10.1126/science.1233989] An algorithm predicts the neutralization specificity of sera from HIV-infected individuals. Perspectives - Neuroscience Why Adults Need New Brain Cells Olaf Bergmann and Jonas Frisén Science 10 May 2013: 695-696.[DOI:10.1126/science.1237976] Neurogenesis and gliogenesis shape connectivity in the adult brain, influencing plasticity and repair. Reports Emergence of Individuality in Genetically Identical Mice Julia Freund, Andreas M. Brandmaier, Lars Lewejohann, Imke Kirste, Mareike Kritzler, Antonio Krüger, Norbert Sachser, Ulman Lindenberger, and Gerd Kempermann Science 10 May 2013: 756-759.[DOI:10.1126/science.1235294] Over time, the brains and behaviors of inbred mice diversify. [Science] 10 May 2013 vol 340, issue 6133, pages 653-776 Reviews Bacterial Subversion of Host Innate Immune Pathways Leigh A. Baxt, Anna Cristina Garza-Mayers, and Marcia B. Goldberg Science 10 May 2013: 697-701.[DOI:10.1126/science.1235771] Cellular Self-Defense: How Cell-Autonomous Immunity Protects Against Pathogens Felix Randow, John D. MacMicking, and Leo C. James Science 10 May 2013: 701-706.[DOI:10.1126/science.1233028] Research Articles Rational HIV Immunogen Design to Target Specific Germline B Cell Receptors Joseph Jardine, Jean-Philippe Julien, Sergey Menis, Takayuki Ota, Oleksandr Kalyuzhniy, Andrew McGuire, Devin Sok, Po-Ssu Huang, Skye MacPherson, Meaghan Jones, Travis Nieusma, John Mathison, David Baker, Andrew B. Ward, Dennis R. Burton, Leonidas Stamatatos, David Nemazee, Ian A. Wilson, and William R. Schief Science 10 May 2013: 711-716. DOI:10.1126/science.1234150] Structural knowledge of broadly neutralizing antibodies against HIV-1 guides the design of an immunogen to elicit them. [Science] 10 May 2013 vol 340, issue 6133, pages 653-776 Reports Robust Circadian Oscillations in Growing Cyanobacteria Require Transcriptional Feedback Shu-Wen Teng, Shankar Mukherji, Jeffrey R. Moffitt, Sophie de Buyl, and Erin K. O’Shea Science 10 May 2013: 737-740.[DOI:10.1126/science.1230996] The cyanobacterial clock uses one circuit for rhythms and a second circuit for intercellular synchronous oscillations. Global Leaf Trait Relationships: Mass, Area, and the Leaf Economics Spectrum Jeanne L. D. Osnas, Jeremy W. Lichstein, Peter B. Reich, and Stephen W. Pacala Science 10 May 2013: 741-744. [DOI:10.1126/science.1231574] Leaf traits are distributed in proportion to area; relationships between leaf traits are independent of leaf mass and area. Early Mesodermal Cues Assign Avian Cardiac Pacemaker Fate Potential in a Tertiary Heart Field Michael Bressan, Gary Liu, and Takashi Mikawa Science 10 May 2013: 744-748. [DOI:10.1126/science.1232877] A region of the lateral plate mesoderm gives rise to the cardiac pacemaker cell lineage prior to the onset of heart formation. Wolbachia Invades Anopheles stephensi Populations and Induces Refractoriness to Plasmodium Infection Guowu Bian, Deepak Joshi, Yuemei Dong, Peng Lu, Guoli Zhou, Xiaoling Pan, Yao Xu, George Dimopoulos, and Zhiyong Xi Science 10 May 2013: 748-751.[DOI:10.1126/science.1236192] Stable inheritance of a symbiotic bacterium suppresses malaria parasites in mosquitoes. Compartmentalization of GABAergic Inhibition by Dendritic Spines Chiayu Q. Chiu, Gyorgy Lur, Thomas M. Morse, Nicholas T. Carnevale, Graham C. R. Ellis-Davies, and Michael J. Higley Science 10 May 2013: 759-762.[DOI:10.1126/science.1234274] Inhibitory synapses can control individual dendritic spines independently from their neighbors. [Science Sig] 7 May 2013 Vol 6, Issue 274 Gene network reconstruction reveals cell cycle and antiviral genes as major drivers of cervical cancer Karina L. Mine,1, 2, 12Natalia Shulzhenko,1, 3, 4, 12Anatoly Yambartsev,5Mark Rochman,6, 13 Gerdine F. O. Sanson,1, 13Malin Lando,7Sudhir Varma,8Jeff Skinner,8Natalia Volfovsky,9 Tao Deng,6Sylvia M. F. Brenna,10Carmen R. N. Carvalho,11Julisa C. L. Ribalta,11Michael Bustin,6Polly Matzinger,3Ismael D. C. G. Silva,11Heidi Lyng,7Maria Gerbase-DeLima1, 2 & Andrey Morgun1, 3, 4 Instituto de Imunogenética—Associação Fundo de Incentivo à Pesquisa (IGEN-AFIP), São Paulo, São Paulo, Brazil Although human papillomavirus was identified as an aetiological factor in cervical cancer, the key human gene drivers of this disease remain unknown. Here we apply an unbiased approach integrating gene expression and chromosomal aberration data. In an independent group of patients, we reconstruct and validate a gene regulatory meta-network, and identify cell cycle and antiviral genes that constitute two major subnetworks upregulated in tumour samples. These genes are located within the same regions as chromosomal amplifications, most frequently on 3q. We propose a model in which selected chromosomal gains drive activation of antiviral genes contributing to episomal virus elimination, which synergizes with cell cycle dysregulation. These findings may help to explain the paradox of episomal human papillomavirus decline in women with invasive cancer who were previously unable to clear the virus. Table of Contents May 1, 2013; 27 (9) The mechanisms by which the p53 tumor suppressor acts remain incompletely understood. To gain new insights into p53 biology, we used high-throughput sequencing to analyze global p53 transcriptional networks in primary mouse embryo fibroblasts in response to DNA damage. Chromatin immunoprecipitation sequencing reveals 4785 p53bound sites in the genome located near 3193 genes involved in diverse biological processes. RNA sequencing analysis shows that only a subset of p53-bound genes is transcriptionally regulated, yielding a list of 432 p53-bound and regulated genes. Interestingly, we identify a host of autophagy genes as direct p53 target genes. While the autophagy program is regulated predominantly by p53, the p53 family members p63 and p73 contribute to activation of this autophagy gene network. Induction of autophagy genes in response to p53 activation is associated with enhanced autophagy in diverse settings and depends on p53 transcriptional activity. While p53-induced autophagy does not affect cell cycle arrest in response to DNA damage, it is important for both robust p53-dependent apoptosis triggered by DNA damage and transformation suppression by p53. Together, our data highlight an intimate connection between p53 and autophagy through a vast transcriptional network and indicate that autophagy contributes to p53-dependent apoptosis and cancer suppression. KJ The Novel Gene tank, a Tumor Suppressor Homolog, Regulates Ethanol Sensitivity in Drosophila Anita V. Devineni, Mark Eddison, and Ulrike Heberlein Abstract In both mammalian and insect models of ethanol intoxication, high doses of ethanol induce motor impairment and eventually sedation. Sensitivity to the sedative effects of ethanol is inversely correlated with risk for alcoholism. However, the genes regulating ethanol sensitivity are largely unknown. Based on a previous genetic screen in Drosophila for ethanol sedation mutants, we identified a novel gene, tank (CG15626), the homolog of the mammalian tumor suppressor EI24/PIG8, which has a strong role in regulating ethanol sedation sensitivity. Genetic and behavioral analyses revealed that tank acts in the adult nervous system to promote ethanol sensitivity. We localized the function of tank in regulating ethanol sensitivity to neurons within the pars intercerebralis that have not been implicated previously in ethanol responses. We show that acutely manipulating the activity of all tank-expressing neurons, or of pars intercerebralis neurons in particular, alters ethanol sensitivity in a sexually dimorphic manner, since neuronal activation enhanced ethanol sedation in males, but not females. Finally, we provide anatomical evidence that tankexpressing neurons form likely synaptic connections with neurons expressing the neural sex determination factor fruitless (fru), which have been implicated recently in the regulation of ethanol sensitivity. We suggest that a functional interaction with fru neurons, many of which are sexually dimorphic, may account for the sex-specific effect induced by activating tank neurons. Overall, we have characterized a novel gene and corresponding set of neurons that regulate ethanol sensitivity in Drosophila. KJ KJ KJ Department of Cell Biology, Albert Einstein College of Medicine, Bronx, New York, USA. How hematopoietic stem cells (HSCs) coordinate the regulation of opposing cellular mechanisms such as self-renewal and differentiation commitment remains unclear. Here we identified the transcription factor and chromatin remodeler Satb1 as a critical regulator of HSC fate. HSCs lacking Satb1 had defective self-renewal, were less quiescent and showed accelerated lineage commitment, which resulted in progressive depletion of functional HSCs. The enhanced commitment was caused by less symmetric self-renewal and more symmetric differentiation divisions of Satb1deficient HSCs. Satb1 simultaneously repressed sets of genes encoding molecules involved in HSC activation and cellular polarity, including Numb and Myc, which encode two key factors for the specification of stem-cell fate. Thus, Satb1 is a regulator that promotes HSC quiescence and represses lineage commitment. Laboratory of Host Defense, World Premier International Research Center Immunology Frontier Research Center, Osaka University, Osaka, Japan. NLRP3 forms an inflammasome with its adaptor ASC, and its excessive activation can cause inflammatory diseases. However, little is known about the mechanisms that control assembly of the inflammasome complex. Here we show that microtubules mediated assembly of the NLRP3 inflammasome. Inducers of the NLRP3 inflammasome caused aberrant mitochondrial homeostasis to diminish the concentration of the coenzyme NAD+, which in turn inactivated the NAD+-dependent α-tubulin deacetylase sirtuin 2; this resulted in the accumulation of acetylated α-tubulin. Acetylated α-tubulin mediated the dynein-dependent transport of mitochondria and subsequent apposition of ASC on mitochondria to NLRP3 on the endoplasmic reticulum. Therefore, in addition to direct activation of NLRP3, the creation of optimal sites for signal transduction by microtubules is required for activation of the entire NLRP3 inflammasome. Department of Immunology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA. NOD2 receptor and the cytosolic protein kinase RIPK2 regulate NF-κB and MAP kinase signaling during bacterial infections, but the role of this immune axis during viral infections has not been addressed. We demonstrate that Nod2−/− and Ripk2−/− mice are hypersusceptible to infection with influenza A virus. Ripk2−/− cells exhibited defective autophagy of mitochondria (mitophagy), leading to enhanced mitochondrial production of superoxide and accumulation of damaged mitochondria, which resulted in greater activation of the NLRP3 inflammasome and production of IL-18. RIPK2 regulated mitophagy in a kinase-dependent manner by phosphorylating the mitophagy inducer ULK1. Accordingly, Ulk1−/− cells exhibited enhanced mitochondrial production of superoxide and activation of caspase-1. These results demonstrate a role for NOD2-RIPK2 signaling in protection against virally triggered immunopathology by negatively regulating activation of the NLRP3 inflammasome and production of IL-18 via ULK1dependent mitophagy.