TY - JOUR AB - Phenotypic drug screening remains constrained by the vastness of chemical space and technical challenges scaling experimental workflows. To overcome these barriers, computational methods have been developed to prioritize compounds, but they rely on either single-task models lacking generalizability or heuristic-based genomic proxies that resist optimization. We designed an active deep-learning framework that leverages omics to enable scalable, optimizable identification of compounds that induce complex phenotypes. Our generalizable algorithm outperformed state-of-the-art models on classical recall, translating to a 13-17x increase in phenotypic hit-rate across two hematological discovery campaigns. Combining this algorithm with a lab-in-the-loop signature refinement step, we achieved an additional two-fold increase in hit-rate and molecular insights. In sum, our framework enables efficient phenotypic hit identification campaigns, with broad potential to accelerate drug discovery. AU - DeMeo, B.* AU - Nesbitt, C.* AU - Miller, S.A.* AU - Burkhardt, D.B.* AU - Lipchina, I.* AU - Fu, D.* AU - Holderreith, P.* AU - Kim, D.* AU - Kolchenko, S.* AU - Szalata, A. AU - Gupta, I.* AU - Kerr, C.* AU - Pfefer, T.J.* AU - Rojas-Rodriguez, R.* AU - Kuppassani, S.* AU - Kruidenier, L.* AU - Doshi, P.B.* AU - Zamanighomi, M.* AU - Collins, J.J.* AU - Shalek, A.K.* AU - Theis, F.J. AU - Cortes, M.* C1 - 75833 C2 - 58128 TI - Active learning framework leveraging transcriptomics identifies modulators of disease phenotypes. JO - Science PY - 2025 SN - 0036-8075 ER - TY - JOUR AB - Aging is a major risk factor for neurodegeneration and is characterized by diverse cellular and molecular hallmarks. To understand the origin of these hallmarks, we studied the effects of aging on the transcriptome, translatome, and proteome in the brain of short-lived killifish. We identified a cascade of events in which aberrant translation pausing led to altered abundance of proteins independently of transcriptional regulation. In particular, aging caused increased ribosome stalling and widespread depletion of proteins enriched in basic amino acids. These findings uncover a potential vulnerable point in the aging brain's biology-the biogenesis of basic DNA and RNA binding proteins. This vulnerability may represent a unifying principle that connects various aging hallmarks, encompassing genome integrity, proteostasis, and the biosynthesis of macromolecules. AU - Di Fraia, D.* AU - Marino, A.* AU - Lee, J.H.* AU - Kelmer Sacramento, E.* AU - Baumgart, M.* AU - Bagnoli, S.* AU - Balla, T.* AU - Schalk, F.* AU - Kamrad, S.* AU - Guan, R.* AU - Caterino, C.* AU - Giannuzzi, C.* AU - Tomaz da Silva, P.* AU - Sahu, A.K.* AU - Gut, H.* AU - Siano, G.* AU - Tiessen, M.* AU - Terzibasi-Tozzini, E.* AU - Fornasiero, E.F.* AU - Gagneur, J. AU - Englert, C.* AU - Patil, K.R.* AU - Correia-Melo, C.* AU - Nedialkova, D.D.* AU - Frydman, J.* AU - Cellerino, A.* AU - Ori, A.* C1 - 75269 C2 - 57882 CY - 1200 New York Ave, Nw, Washington, Dc 20005 Usa TI - Altered translation elongation contributes to key hallmarks of aging in the killifish brain. JO - Science VL - 389 IS - 6759 PB - Amer Assoc Advancement Science PY - 2025 SN - 0036-8075 ER - TY - JOUR AB - Single-cell transcriptomics (scRNA-seq) has facilitated the characterization of cell state heterogeneity and recapitulation of differentiation trajectories. However, the exclusive use of mRNA measurements comes at the risk of missing important biological information. Here we leveraged recent technological advances in single-cell proteomics by Mass Spectrometry (scp-MS) to generate an scp-MS dataset of an in vivo differentiation hierarchy encompassing over 2500 human CD34+ hematopoietic stem and progenitor cells. Through integration with scRNA-seq, we identified proteins that are important for stem cell function, which were not indicated by their mRNA transcripts. Further, we showed that modeling translation dynamics can infer cell progression during differentiation and explain substantially more protein variation from mRNA than linear correlation. Our work offers a framework for single-cell multi-omics studies across biological systems. AU - Furtwangler, B.* AU - Uresin, N.* AU - Richter, S. AU - Schuster, M.B.* AU - Barmpouri, D.* AU - Holze, H.* AU - Wenzel, A.* AU - Grønbæk, K.* AU - Theilgaard-Mönch, K.* AU - Theis, F.J. AU - Schoof, E.M.* AU - Porse, B.T.* C1 - 75381 C2 - 57953 TI - Mapping early human blood cell differentiation using single-cell proteomics and transcriptomics. JO - Science VL - 390 IS - 6770 PY - 2025 SN - 0036-8075 ER - TY - JOUR AB - Stem cells are a promising source for cellular therapies across many diseases and tissues. Their inherent ability to differentiate into other cell types has been the focus of investigation over decades. This ability is currently being exploited for therapies using strategies to repair or replace damaged tissues and cells or to alleviate immune rejection. Exploring stem cell function has enabled direct reprogramming approaches, for example, through the production of induced pluripotent stem cells and the generation of tissue-specific stem cells. Understanding stem cell function has emerged as an important strategy for repopulating stem cell pools or generating differentiated cells for therapy. Here, we review general principles of mammalian stem cell biology and cellular reprogramming approaches and their use for current and future therapeutic purposes. AU - Götz, M. AU - Torres-Padilla, M.E. C1 - 74247 C2 - 57100 CY - 1200 New York Ave, Nw, Washington, Dc 20005 Usa TI - Stem cells as role models for reprogramming and repair. JO - Science VL - 388 IS - 6746 PB - Amer Assoc Advancement Science PY - 2025 SN - 0036-8075 ER - TY - JOUR AB - Androgens are pleiotropic and play pivotal roles in the formation and variation of sexual phenotypes. We show that differences in circulating androgens between the three male mating morphs in ruff sandpipers are linked to 17-beta hydroxysteroid dehydrogenase 2 (HSD17B2), encoded by a gene within the supergene that determines the morphs. Low-testosterone males had higher HSD17B2 expression in blood than high-testosterone males, as well as in brain areas related to social behaviors and testosterone production. Derived HSD17B2 isozymes, which are absent in high-testosterone males but preferentially expressed in low-testosterone males, converted testosterone to androstenedione faster than the ancestral isozyme. Thus, a combination of evolutionary changes in regulation, sequence, and structure of a single gene introduces endocrine variation underlying reproductive phenotypes. AU - Loveland, J.L.* AU - Zemella, A.* AU - Jovanović, V.M.* AU - Möller, G. AU - Sager, C.P.* AU - Bastos, B.* AU - Dyar, K.A. AU - Fusani, L.* AU - Gahr, M.* AU - Giraldo-Deck, L.M.* AU - Goymann, W.* AU - Lank, D.B.* AU - Tokarz, J. AU - Nowick, K.* AU - Küpper, C.* C1 - 73147 C2 - 56927 CY - 1200 New York Ave, Nw, Washington, Dc 20005 Usa SP - 406-412 TI - A single gene orchestrates androgen variation underlying male mating morphs in ruffs. JO - Science VL - 387 IS - 6732 PB - Amer Assoc Advancement Science PY - 2025 SN - 0036-8075 ER - TY - JOUR AB - Mitochondria regenerate adenosine triphosphate (ATP) through oxidative phosphorylation. This process is carried out by five membrane-bound complexes collectively known as the respiratory chain, working in concert to transfer electrons and pump protons. The precise organization of these complexes in native cells is debated. We used in situ cryo-electron tomography to visualize the native structures and organization of several major mitochondrial complexes in Chlamydomonas reinhardtii cells. ATP synthases and respiratory complexes segregate into curved and flat crista membrane domains, respectively. Respiratory complexes I, III, and IV assemble into a respirasome supercomplex, from which we determined a native 5-angstrom (Å) resolution structure showing binding of electron carrier cytochrome c. Combined with single-particle cryo-electron microscopy at 2.4-Å resolution, we model how the respiratory complexes organize inside native mitochondria. AU - Waltz, F.* AU - Righetto, R.D.* AU - Lamm, L. AU - Salinas-Giegé, T.* AU - Kelley, R.K.* AU - Zhang, X.* AU - Obr, M.* AU - Khavnekar, S.* AU - Kotecha, A.* AU - Engel, B.D.* C1 - 73724 C2 - 57192 CY - 1200 New York Ave, Nw, Washington, Dc 20005 Usa SP - 1296-1301 TI - In-cell architecture of the mitochondrial respiratory chain. JO - Science VL - 387 IS - 6740 PB - Amer Assoc Advancement Science PY - 2025 SN - 0036-8075 ER - TY - JOUR AB - Size and shape are critical discriminators between molecular species and states. We describe a microchip-based high-throughput imaging approach offering rapid and precise determination of molecular properties under native solution conditions. Our method detects differences in molecular weight across at least three orders of magnitude and down to two carbon atoms in small molecules. We quantify the strength of molecular interactions across more than six orders of magnitude in affinity constant and track reactions in real time. Highly parallel measurements on individual molecules serve to characterize sample-state heterogeneity at the highest resolution, offering predictive input to model three-dimensional structure. We further leverage the method's structural sensitivity for diagnostics, exploiting ligand-induced conformational changes in the insulin receptor to sense insulin concentration in serum at the subnanoliter and subzeptomole scale. AU - Zhu, X.* AU - Bennett, T.J.D.* AU - Zouboulis, K.C.* AU - Soulias, D.* AU - Grzybek, M.* AU - Benesch, J.L.P.* AU - El-Sagheer, A.H.* AU - Coskun, Ü. AU - Krishnan, M.* C1 - 74425 C2 - 57443 CY - 1200 New York Ave, Nw, Washington, Dc 20005 Usa TI - Measurements of molecular size and shape on a chip. JO - Science VL - 388 IS - 6747 PB - Amer Assoc Advancement Science PY - 2025 SN - 0036-8075 ER - TY - JOUR AB - Humans with monogenic inborn errors responsible for extreme disease phenotypes can reveal essential physiological pathways. We investigated germline mutations in GNAI2, which encodes Gαi2, a key component in heterotrimeric G protein signal transduction usually thought to regulate adenylyl cyclase-mediated cyclic adenosine monophosphate (cAMP) production. Patients with activating Gαi2 mutations had clinical presentations that included impaired immunity. Mutant Gαi2 impaired cell migration and augmented responses to T cell receptor (TCR) stimulation. We found that mutant Gαi2 influenced TCR signaling by sequestering the guanosine triphosphatase (GTPase)-activating protein RASA2, thereby promoting RAS activation and increasing downstream extracellular signal-regulated kinase (ERK)/mitogen-activated protein kinase (MAPK) and phosphatidylinositol 3-kinase (PI3K)-AKT S6 signaling to drive cellular growth and proliferation. AU - Ham, H.* AU - Jing, H.* AU - Lamborn, I.T.* AU - Kober, M.M.* AU - Koval, A.* AU - Berchiche, Y.A.* AU - Anderson, D.E.* AU - Druey, K.M.* AU - Mandl, J.N.* AU - Isidor, B.* AU - Ferreira, C.R.* AU - Freeman, A.F.* AU - Ganesan, S.* AU - Karsak, M.* AU - Mustillo, P.J.* AU - Teo, J.* AU - Zolkipli-Cunningham, Z.* AU - Chatron, N.* AU - Lecoquierre, F.* AU - Oler, A.J.* AU - Schmid, J.P.* AU - Kuhns, D.B.* AU - Xu, X.* AU - Hauck, F.* AU - Al-Herz, W.* AU - Wagner, M. AU - Terhal, P.A.* AU - Muurinen, M.* AU - Barlogis, V.* AU - Cruz, P.* AU - Danielson, J.* AU - Stewart, H.* AU - Loid, P.* AU - Rading, S.* AU - Keren, B.* AU - Pfundt, R.* AU - Zarember, K.A.* AU - Vill, K.* AU - Potocki, L.* AU - Olivier, K.N.* AU - Lesca, G.* AU - Faivre, L.* AU - Wong, M.* AU - Puel, A.* AU - Chou, J.* AU - Tusseau, M.* AU - Moutsopoulos, N.M.* AU - Matthews, H.F.* AU - Simons, C.* AU - Taft, R.J.* AU - Soldatos, A.* AU - Masle-Farquhar, E.* AU - Pittaluga, S.* AU - Brink, R.* AU - Fink, D.L.* AU - Kong, H.H.* AU - Kabat, J.* AU - Kim, W.S.* AU - Bierhals, T.* AU - Meguro, K.* AU - Hsu, A.P.* AU - Gu, J.* AU - Stoddard, J.* AU - Banos-Pinero, B.* AU - Slack, M.* AU - Trivellin, G.* AU - Mazel, B.* AU - Soomann, M.* AU - Li, S.* AU - Watts, V.J.* AU - Stratakis, C.A.* AU - Rodriguez-Quevedo, M.F.* AU - Bruel, A.L.* AU - Lipsanen-Nyman, M.* AU - Saultier, P.* AU - Jain, R.* AU - Lehalle, D.* AU - Torres, D.* AU - Sullivan, K.E.* AU - Barbarot, S.* AU - Neu, A.* AU - Duffourd, Y.* AU - Similuk, M.* AU - McWalter, K.* AU - Blanc, P.D.* AU - Bézieau, S.* AU - Jin, T.* AU - Geha, R.S.* AU - Casanova, J.L.* AU - Mäkitie, O.M.* AU - Kubisch, C.* AU - Edery, P.* AU - Christodoulou, J.* AU - Germain, R.N.* AU - Goodnow, C.C.* AU - Sakmar, T.P.* AU - Billadeau, D.D.* AU - Küry, S.* AU - Katanaev, V.L.* AU - Zhang, Y.* AU - Lenardo, M.J.* AU - Su, H.C.* C1 - 71745 C2 - 56424 CY - 1200 New York Ave, Nw, Washington, Dc 20005 Usa TI - Germline mutations in a G protein identify signaling cross-talk in T cells. JO - Science VL - 385 IS - 6715 PB - Amer Assoc Advancement Science PY - 2024 SN - 0036-8075 ER - TY - JOUR AB - Brown adipose tissue (BAT) is a heater organ that expresses thermogenic uncoupling protein 1 (UCP1) to maintain high body temperatures during cold stress. BAT thermogenesis is considered an overarching mammalian trait, but its evolutionary origin is unknown. We show that adipose tissue of marsupials, which diverged from eutherian mammals ~150 million years ago, expresses a nonthermogenic UCP1 variant governed by a partial transcriptomic BAT signature similar to that found in eutherian beige adipose tissue. We found that the reconstructed UCP1 sequence of the common eutherian ancestor displayed typical thermogenic activity, whereas therian ancestor UCP1 is nonthermogenic. Thus, mammalian adipose tissue thermogenesis may have evolved in two distinct stages, with a prethermogenic stage in the common therian ancestor linking UCP1 expression to adipose tissue and thermal stress. We propose that in a second stage, UCP1 acquired its thermogenic function specifically in eutherians, such that the onset of mammalian BAT thermogenesis occurred only after the divergence from marsupials. AU - Keipert, S.* AU - Gaudry, M.J.* AU - Kutschke, M.* AU - Keuper, M.* AU - Dela Rosa, M.A.S.* AU - Cheng, Y. AU - Monroy Kuhn, J.M. AU - Laterveer, R.* AU - Cotrim, C.A.* AU - Giere, P.* AU - Perocchi, F. AU - Feederle, R. AU - Crichton, P.G.* AU - Lutter, D. AU - Jastroch, M.* C1 - 70968 C2 - 55841 CY - 1200 New York Ave, Nw, Washington, Dc 20005 Usa SP - 1111-1117 TI - Two-stage evolution of mammalian adipose tissue thermogenesis. JO - Science VL - 384 IS - 6700 PB - Amer Assoc Advancement Science PY - 2024 SN - 0036-8075 ER - TY - JOUR AB - Despite continuous expansion of the RNA-binding protein (RBP) world, there is a lack of systematic understanding of RBPs in mammalian testis, which harbors one of the most complex tissue transcriptomes. We adapted RNA interactome capture to mouse male germ cells, building an RBP atlas characterized by multiple layers of dynamics along spermatogenesis. Trapping of RNA-crosslinked peptides showed that the glutamic acid-arginine (ER) patch, a residue-coevolved polyampholytic element present in coiled-coils, enhances RNA binding of its host RBPs. Deletion of this element in NONO (non-POU domain-containing octamer-binding protein) led to a defective mitosis-to-meiosis transition due to compromised NONO-RNA interactions. Whole-exome sequencing of over 1000 infertile men revealed a prominent role of RBPs in the human genetic architecture of male infertility and identified risk ER patch variants. AU - Li, Y.* AU - Wang, Y.* AU - Tan, Y.Q.* AU - Yue, Q.* AU - Guo, Y.* AU - Yan, R.* AU - Meng, L.* AU - Zhai, H.* AU - Tong, L.* AU - Yuan, Z.* AU - Li, W.* AU - Wang, C.* AU - Han, S.* AU - Ren, S.* AU - Yan, Y.* AU - Wang, W. AU - Gao, L.* AU - Tan, C.* AU - Hu, T.* AU - Zhang, H.* AU - Liu, L.* AU - Yang, P.* AU - Jiang, W.* AU - Ye, Y.* AU - Tan, H.* AU - Wang, Y.* AU - Lu, C.* AU - Li, X.* AU - Xie, J.* AU - Yuan, G.* AU - Cui, Y.* AU - Shen, B.* AU - Guan, Y.* AU - Shi, Q.* AU - Lin, G.* AU - Ni, T.* AU - Sun, Z.* AU - Ye, L.* AU - Vourekas, A.* AU - Guo, X.* AU - Lin, M.* AU - Zheng, K.* C1 - 71551 C2 - 56276 TI - The landscape of RNA-binding proteins in mammalian spermatogenesis. JO - Science VL - 386 IS - 6720 PY - 2024 SN - 0036-8075 ER - TY - JOUR AB - Following infection of B cells, Epstein Barr virus (EBV) engages host pathways that mediate cell proliferation and transformation, contributing to the propensity of the virus to drive immune dysregulation and lymphomagenesis. We found that the EBV protein EBNA2 initiates NAD de novo biosynthesis by driving expression of the metabolic enzyme IDO1 in infected B cells. Virus-enforced NAD production sustained mitochondrial complex I activity, to match ATP-production with bioenergetic requirements of proliferation and transformation. In transplant patients, IDO1 expression in EBV-infected B cells, and a serum signature of increased IDO1 activity, preceded development of lymphoma. In humanized mice infected with EBV, IDO1 inhibition reduced both viremia and lymphomagenesis. Virus-orchestrated NAD biosynthesis is, thus, a druggable metabolic vulnerability of EBV-driven B cell transformation-opening therapeutic possibilities for EBV-related diseases. AU - Müller-Durovic, B.* AU - Jäger, J.* AU - Engelmann, C.* AU - Schuhmachers, P.* AU - Altermatt, S.* AU - Schlup, Y.* AU - Duthaler, U.* AU - Makowiec, C.* AU - Unterstab, G.* AU - Roffeis, S.* AU - Xhafa, E.* AU - Assmann, N.* AU - Trulsson, F.* AU - Steiner, R.* AU - Edwards-Hicks, J.* AU - West, J.* AU - Turner, L.* AU - Develioglu, L.* AU - Ivanek, R.* AU - Azzi, T.* AU - Dehio, P.* AU - Berger, C.* AU - Kuzmin, D.* AU - Saboz, S.* AU - Mautner, J. AU - Löliger, J.* AU - Geigges, M.* AU - Palianina, D.* AU - Khanna, N.* AU - Dirnhofer, S.* AU - Münz, C.* AU - Bantug, G.R.* AU - Hess, C.* AU - Koller, M.* AU - Rossi, S.* AU - Stampf, S.* AU - Müller, N.J.* C1 - 70728 C2 - 55728 TI - A metabolic dependency of EBV can be targeted to hinder B cell transformation. JO - Science VL - 385 IS - 6704 PY - 2024 SN - 0036-8075 ER - TY - JOUR AB - Immune homeostasis requires a balance of inflammatory and suppressive activities. To design cells potentially useful for local immune suppression, we engineered conventional CD4+ T cells with synthetic Notch (synNotch) receptors driving antigen-triggered production of anti-inflammatory payloads. Screening a diverse library of suppression programs, we observed the strongest suppression of cytotoxic T cell attack by the production of both anti-inflammatory factors (interleukin-10, transforming growth factor-β1, programmed death ligand 1) and sinks for proinflammatory cytokines (interleukin-2 receptor subunit CD25). Engineered cells with bespoke regulatory programs protected tissues from immune attack without systemic suppression. Synthetic suppressor T cells protected transplanted beta cell organoids from cytotoxic T cells. They also protected specific tissues from unwanted chimeric antigen receptor (CAR) T cell cross-reaction. Synthetic suppressor T cells are a customizable platform to potentially treat autoimmune diseases, organ rejection, and CAR T cell toxicities with spatial precision. AU - Reddy, N.R.* AU - Maachi, H. AU - Xiao, Y.* AU - Simic, M.S.* AU - Yu, W.* AU - Tonai, Y.* AU - Cabanillas, D.A.* AU - Serrano-Wu, E.* AU - Pauerstein, P.T.* AU - Tamaki, W.* AU - Allen, G.M.* AU - Parent, A.V.* AU - Hebrok, M. AU - Lim, W.A.* C1 - 72982 C2 - 56764 CY - 1200 New York Ave, Nw, Washington, Dc 20005 Usa TI - Engineering synthetic suppressor T cells that execute locally targeted immunoprotective programs. JO - Science VL - 386 IS - 6726 PB - Amer Assoc Advancement Science PY - 2024 SN - 0036-8075 ER - TY - JOUR AB - Genomic DNA that resides in the nuclei of mammalian neurons can be as old as the organism itself. The life span of nuclear RNAs, which are critical for proper chromatin architecture and transcription regulation, has not been determined in adult tissues. In this work, we identified and characterized nuclear RNAs that do not turn over for at least 2 years in a subset of postnatally born cells in the mouse brain. These long-lived RNAs were stably retained in nuclei in a neural cell type-specific manner and were required for the maintenance of heterochromatin. Thus, the life span of neural cells may depend on both the molecular longevity of DNA for the storage of genetic information and also the extreme stability of RNA for the functional organization of chromatin. AU - Zocher, S.* AU - McCloskey, A.* AU - Karasinsky, A.* AU - Schulte, R.* AU - Friedrich, U.A. AU - Lesche, M.* AU - Rund, N.* AU - Gage, F.H.* AU - Hetzer, M.W.* AU - Toda, T.* C1 - 70434 C2 - 55620 CY - 1200 New York Ave, Nw, Washington, Dc 20005 Usa SP - 53-59 TI - Lifelong persistence of nuclear RNAs in the mouse brain. JO - Science VL - 384 IS - 6691 PB - Amer Assoc Advancement Science PY - 2024 SN - 0036-8075 ER - TY - JOUR AB - The Hayabusa2 spacecraft collected samples from the surface of the carbonaceous near-Earth asteroid (162173) Ryugu and brought them to Earth. The samples were expected to contain organic molecules, which record processes that occurred in the early Solar System. We analyzed organic molecules extracted from the Ryugu surface samples. We identified a variety of molecules containing the atoms CHNOS, formed by methylation, hydration, hydroxylation, and sulfurization reactions. Amino acids, aliphatic amines, carboxylic acids, polycyclic aromatic hydrocarbons, and nitrogen-heterocyclic compounds were detected, which had properties consistent with an abiotic origin. These compounds likely arose from an aqueous reaction on Ryugu's parent body and are similar to the organics in Ivuna-type meteorites. These molecules can survive on the surfaces of asteroids and be transported throughout the Solar System. AU - Naraoka, H.* AU - Takano, Y.* AU - Dworkin, J.P.* AU - Oba, Y.* AU - Hamase, K.* AU - Furusho, A.* AU - Ogawa, N.O.* AU - Hashiguchi, M.* AU - Fukushima, K.* AU - Aoki, D.* AU - Schmitt-Kopplin, P. AU - Aponte, J.C.* AU - Parker, E.T.* AU - Glavin, D.P.* AU - Mclain, H.L.* AU - Elsila, J.E.* AU - Graham, H.V.* AU - Eiler, J.M.* AU - Orthous-Daunay, F.R.* AU - Wolters, C.* AU - Isa, J.* AU - Vuitton, V.* AU - Thissen, R.* AU - Sakai, S.* AU - Yoshimura, T.* AU - Koga, T.* AU - Ohkouchi, N.* AU - Chikaraishi, Y.* AU - Sugahara, H.* AU - Mita, H.* AU - Furukawa, Y.* AU - Hertkorn, N. AU - Ruf, A.* AU - Yurimoto, H.* AU - Nakamura, T.* AU - Noguchi, T.* AU - Okazaki, R.* AU - Yabuta, H.* AU - Sakamoto, K.* AU - Tachibana, S.* AU - Connolly, H.C.* AU - Lauretta, D.S.* AU - Abe, M.* AU - Yada, T.* AU - Nishimura, M.* AU - Yogata, K.* AU - Nakato, A.* AU - Yoshitake, M.* AU - Suzuki, A.* AU - Miyazaki, A.* AU - Furuya, S.* AU - Hatakeda, K.* AU - Soejima, H.* AU - Hitomi, Y.* AU - Kumagai, K.* AU - Usui, T.* AU - Hayashi, T.* AU - Yamamoto, D.* AU - Fukai, R.* AU - Kitazato, K.* AU - Sugita, S.* AU - Namiki, N.* AU - Arakawa, M.* AU - Ikeda, H.* AU - Ishiguro, M.* AU - Hirata, N.* AU - Wada, K.* AU - Ishihara, Y.* AU - Noguchi, R.* AU - Morota, T.* AU - Sakatani, N.* AU - Matsumoto, K.* AU - Senshu, H.* AU - Honda, R.* AU - Tatsumi, E.* AU - Yokota, Y.* AU - Honda, C.* AU - Michikami, T.* AU - Matsuoka, M.* AU - Miura, A.* AU - Noda, H.* AU - Yamada, T.* AU - Yoshihara, K.* AU - Kawahara, K.* AU - Ozaki, M.* AU - Iijima, Y.I.* AU - Yano, H.* AU - Hayakawa, M.* AU - Iwata, T.* AU - Tsukizaki, R.* AU - Sawada, H.* AU - Hosoda, S.* AU - Ogawa, K.* AU - Okamoto, C.* AU - Shirai, K.* AU - Shimaki, Y.* AU - Yamada, M.* AU - Okada, T.* AU - Yamamoto, Y.* AU - Takeuchi, H.* AU - Fujii, A.* AU - Takei, Y.* AU - Yoshikawa, K.* AU - Mimasu, Y.* AU - Ono, G.* AU - Ogawa, N.* AU - Kikuchi, S.* AU - Nakazawa, S.* AU - Terui, F.* AU - Tanaka, S.* AU - Saiki, T.* AU - Yoshikawa, M.* AU - Watanabe, S.i.* AU - Tsuda, Y.* C1 - 67538 C2 - 54101 CY - 1200 New York Ave, Nw, Washington, Dc 20005 Usa TI - Soluble organic molecules in samples of the carbonaceous asteroid (162173) Ryugu. JO - Science VL - 379 IS - 6634 PB - Amer Assoc Advancement Science PY - 2023 SN - 0036-8075 ER - TY - JOUR AB - Aging is associated with changes in circulating levels of various molecules, some of which remain undefined. We find that concentrations of circulating taurine decline with aging in mice, monkeys, and humans. A reversal of this decline through taurine supplementation increased the health span (the period of healthy living) and life span in mice and health span in monkeys. Mechanistically, taurine reduced cellular senescence, protected against telomerase deficiency, suppressed mitochondrial dysfunction, decreased DNA damage, and attenuated inflammaging. In humans, lower taurine concentrations correlated with several age-related diseases and taurine concentrations increased after acute endurance exercise. Thus, taurine deficiency may be a driver of aging because its reversal increases health span in worms, rodents, and primates and life span in worms and rodents. Clinical trials in humans seem warranted to test whether taurine deficiency might drive aging in humans. AU - Singh, P.* AU - Gollapalli, K.* AU - Mangiola, S.* AU - Schranner, D. AU - Yusuf, M.A.* AU - Chamoli, M.* AU - Shi, S.L.* AU - Lopes Bastos, B.* AU - Nair, T.* AU - Riermeier, A.* AU - Vayndorf, E.M.* AU - Wu, J.Z.* AU - Nilakhe, A.* AU - Nguyen, C.Q.* AU - Muir, M.* AU - Kiflezghi, M.G.* AU - Foulger, A.* AU - Junker, A.* AU - Devine, J.* AU - Sharan, K.* AU - Chinta, S.J.* AU - Rajput, S.* AU - Rane, A.* AU - Baumert, P.* AU - Schönfelder, M.* AU - Iavarone, F.* AU - di Lorenzo, G.* AU - Kumari, S.* AU - Gupta, A.* AU - Sakar, R.* AU - Khyriem, C.* AU - Chawla, A.S.* AU - Sharma, A.* AU - Sarper, N.* AU - Chattopadhyay, N.* AU - Biswal, B.K.* AU - Settembre, C.* AU - Nagarajan, P.* AU - Targoff, K.L.* AU - Picard, M.* AU - Gupta, S.* AU - Velagapudi, V.* AU - Papenfuss, A.T.* AU - Kaya, A.* AU - Ferreira, M.G.* AU - Kennedy, B.K.* AU - Andersen, J.K.* AU - Lithgow, G.J.* AU - Ali, A.M.* AU - Mukhopadhyay, A.* AU - Palotie, A.* AU - Kastenmüller, G. AU - Kaeberlein, M.* AU - Wackerhage, H.* AU - Pal, B.* AU - Yadav, V.K.* C1 - 67841 C2 - 54319 CY - 1200 New York Ave, Nw, Washington, Dc 20005 Usa TI - Taurine deficiency as a driver of aging. JO - Science VL - 380 IS - 6649 PB - Amer Assoc Advancement Science PY - 2023 SN - 0036-8075 ER - TY - JOUR AB - Cell-cell interactions in the central nervous system play important roles in neurologic diseases. However, little is known about the specific molecular pathways involved, and methods for their systematic identification are limited. Here, we developed a forward genetic screening platform that combines CRISPR-Cas9 perturbations, cell coculture in picoliter droplets, and microfluidic-based fluorescence-activated droplet sorting to identify mechanisms of cell-cell communication. We used SPEAC-seq (systematic perturbation of encapsulated associated cells followed by sequencing), in combination with in vivo genetic perturbations, to identify microglia-produced amphiregulin as a suppressor of disease-promoting astrocyte responses in multiple sclerosis preclinical models and clinical samples. Thus, SPEAC-seq enables the high-throughput systematic identification of cell-cell communication mechanisms. AU - Wheeler, M.A.* AU - Clark, I.C.* AU - Lee, H.G.* AU - Li, Z.* AU - Linnerbauer, M.* AU - Rone, J.M.* AU - Blain, M.* AU - Akl, C.F.* AU - Piester, G.* AU - Giovannoni, F.* AU - Charabati, M.* AU - Lee, J.H.* AU - Kye, Y.C.* AU - Choi, J.* AU - Sanmarco, L.M.* AU - Srun, L.* AU - Chung, E.N.* AU - Flausino, L.E.* AU - Andersen, B.M.* AU - Rothhammer, V.* AU - Yano, H.* AU - Illouz, T.* AU - Zandee, S.E.J.* AU - Daniel, C. AU - Artis, D.* AU - Prinz, M.* AU - Abate, A.R.* AU - Kuchroo, V.K.* AU - Antel, J.P.* AU - Prat, A.* AU - Quintana, F.J.* C1 - 67743 C2 - 54052 CY - 1200 New York Ave, Nw, Washington, Dc 20005 Usa SP - 1023-1030 TI - Droplet-based forward genetic screening of astrocyte-microglia cross-talk. JO - Science VL - 379 IS - 6636 PB - Amer Assoc Advancement Science PY - 2023 SN - 0036-8075 ER - TY - JOUR AB - Polycyclic aromatic hydrocarbons (PAHs) contain ≲20% of the carbon in the interstellar medium. They are potentially produced in circumstellar environments (at temperatures ≳1000 kelvin), by (~10 kelvin) interstellar clouds, or by processing of carbon-rich dust grains. We report isotopic properties of PAHs extracted from samples of the asteroid Ryugu and the meteorite Murchison. The doubly-13C substituted compositions (Δ2×13C values) of the PAHs naphthalene, fluoranthene, and pyrene are 9 to 51‰ higher than values expected for a stochastic distribution of isotopes. The Δ2×13C values are higher than expected if the PAHs formed in a circumstellar environment, but consistent with formation in the interstellar medium. By contrast, the PAHs phenanthrene and anthracene in Ryugu samples have Δ2×13C values consistent with formation by higher-temperature reactions. AU - Zeichner, S.S.* AU - Aponte, J.C.* AU - Bhattacharjee, S.* AU - Dong, G.* AU - Hofmann, A.E.* AU - Dworkin, J.P.* AU - Glavin, D.P.* AU - Elsila, J.E.* AU - Graham, H.V.* AU - Naraoka, H.* AU - Takano, Y.* AU - Tachibana, S.* AU - Karp, A.T.* AU - Grice, K.* AU - Holman, A.I.* AU - Freeman, K.H.* AU - Yurimoto, H.* AU - Nakamura, T.* AU - Noguchi, T.* AU - Okazaki, R.* AU - Yabuta, H.* AU - Sakamoto, K.* AU - Yada, T.* AU - Nishimura, M.* AU - Nakato, A.* AU - Miyazaki, A.* AU - Yogata, K.* AU - Abe, M.* AU - Okada, T.* AU - Usui, T.* AU - Yoshikawa, M.* AU - Saiki, T.* AU - Tanaka, S.* AU - Terui, F.* AU - Nakazawa, S.* AU - Watanabe, S.i.* AU - Tsuda, Y.* AU - Hamase, K.* AU - Fukushima, K.* AU - Aoki, D.* AU - Hashiguchi, M.* AU - Mita, H.* AU - Chikaraishi, Y.* AU - Ohkouchi, N.* AU - Ogawa, N.O.* AU - Sakai, S.* AU - Parker, E.T.* AU - Mclain, H.L.* AU - Orthous-Daunay, F.R.* AU - Vuitton, V.* AU - Wolters, C.* AU - Schmitt-Kopplin, P. AU - Hertkorn, N. AU - Thissen, R.* AU - Ruf, A.* AU - Isa, J.* AU - Oba, Y.* AU - Koga, T.* AU - Yoshimura, T.* AU - Araoka, D.* AU - Sugahara, H.* AU - Furusho, A.* AU - Furukawa, Y.* AU - Aoki, J.* AU - Kano, K.* AU - Nomura, S.M.* AU - Sasaki, K.* AU - Sato, H.* AU - Yoshikawa, T.* AU - Morita, M.* AU - Onose, M.* AU - Kabashima, F.* AU - Fujishima, K.* AU - Yamazaki, T.* AU - Kimura, Y.* AU - Eiler, J.M.* C1 - 69051 C2 - 53829 CY - 1200 New York Ave, Nw, Washington, Dc 20005 Usa SP - 1411-1416 TI - Polycyclic aromatic hydrocarbons in samples of Ryugu formed in the interstellar medium. JO - Science VL - 382 IS - 6677 PB - Amer Assoc Advancement Science PY - 2023 SN - 0036-8075 ER - TY - JOUR AB - Disruption of the physiologic sleep-wake cycle and low melatonin levels frequently accompany cardiac disease, yet the underlying mechanism has remained enigmatic. Immunostaining of sympathetic axons in optically cleared pineal glands from humans and mice with cardiac disease revealed their substantial denervation compared with controls. Spatial, single-cell, nuclear, and bulk RNA sequencing traced this defect back to the superior cervical ganglia (SCG), which responded to cardiac disease with accumulation of inflammatory macrophages, fibrosis, and the selective loss of pineal gland-innervating neurons. Depletion of macrophages in the SCG prevented disease-associated denervation of the pineal gland and restored physiological melatonin secretion. Our data identify the mechanism by which diurnal rhythmicity in cardiac disease is disturbed and suggest a target for therapeutic intervention. AU - Ziegler, K.A.* AU - Ahles, A.* AU - Dueck, A.* AU - Esfandyari, D.* AU - Pichler, P.* AU - Weber, K.* AU - Kotschi, S.* AU - Bartelt, A. AU - Sinicina, I.* AU - Graw, M.* AU - Leonhardt, H.* AU - Weckbach, L.T.* AU - Massberg, S.* AU - Schifferer, M.* AU - Simons, M.* AU - Höher, L. AU - Luo AU - Ertürk, A. AU - Schiattarella, G.G.* AU - Sassi, Y.* AU - Misgeld, T.* AU - Engelhardt, S.* C1 - 68083 C2 - 54561 CY - 1200 New York Ave, Nw, Washington, Dc 20005 Usa SP - 285-290 TI - Immune-mediated denervation of the pineal gland underlies sleep disturbance in cardiac disease. JO - Science VL - 381 IS - 6655 PB - Amer Assoc Advancement Science PY - 2023 SN - 0036-8075 ER - TY - JOUR AB - The observation of genetic correlations between disparate human traits has been interpreted as evidence of widespread pleiotropy. Here, we introduce cross-trait assortative mating (xAM) as an alternative explanation. We observe that xAM affects many phenotypes and that phenotypic cross-mate correlation estimates are strongly associated with genetic correlation estimates (R2 = 74%). We demonstrate that existing xAM plausibly accounts for substantial fractions of genetic correlation estimates and that previously reported genetic correlation estimates between some pairs of psychiatric disorders are congruent with xAM alone. Finally, we provide evidence for a history of xAM at the genetic level using cross-trait even/odd chromosome polygenic score correlations. Together, our results demonstrate that previous reports have likely overestimated the true genetic similarity between many phenotypes. AU - Border, R.* AU - Athanasiadis, G.I.* AU - Buil, A.* AU - Schork, A.J.* AU - Cai, N. AU - Young, A.I.* AU - Werge, T.* AU - Flint, J.* AU - Kendler, K.S.* AU - Sankararaman, S.* AU - Dahl, A.W.* AU - Zaitlen, N.A.* C1 - 66762 C2 - 53297 CY - 1200 New York Ave, Nw, Washington, Dc 20005 Usa SP - 754-761 TI - Cross-trait assortative mating is widespread and inflates genetic correlation estimates. JO - Science VL - 378 IS - 6621 PB - Amer Assoc Advancement Science PY - 2022 SN - 0036-8075 ER - TY - JOUR AB - The centrosome provides an intracellular anchor for the cytoskeleton, regulating cell division, cell migration, and cilia formation. We used spatial proteomics to elucidate protein interaction networks at the centrosome of human induced pluripotent stem cell-derived neural stem cells (NSCs) and neurons. Centrosome-associated proteins were largely cell type-specific, with protein hubs involved in RNA dynamics. Analysis of neurodevelopmental disease cohorts identified a significant overrepresentation of NSC centrosome proteins with variants in patients with periventricular heterotopia (PH). Expressing the PH-associated mutant pre-mRNA-processing factor 6 (PRPF6) reproduced the periventricular misplacement in the developing mouse brain, highlighting missplicing of transcripts of a microtubule-associated kinase with centrosomal location as essential for the phenotype. Collectively, cell type-specific centrosome interactomes explain how genetic variants in ubiquitous proteins may convey brain-specific phenotypes. AU - O'Neill, A.C. AU - Uzbas, F. AU - Antognolli, G. AU - Merino, F.L. AU - Draganova, K. AU - Jäck, A. AU - Zhang, S.* AU - Pedini, G.* AU - Schessner, J.P.* AU - Cramer, K.* AU - Schepers, A. AU - Metzger, F. AU - Esgleas Izquierdo, M. AU - Smialowski, P. AU - Guerrini, R.* AU - Falk, S. AU - Feederle, R.* AU - Freytag, S.* AU - Wang, Z.* AU - Bahlo, M.* AU - Jungmann, R.* AU - Bagni, C.* AU - Borner, G.H.H.* AU - Robertson, S.P.* AU - Hauck, S.M. AU - Götz, M. C1 - 65510 C2 - 52322 TI - Spatial centrosome proteome of human neural cells uncovers disease-relevant heterogeneity. JO - Science VL - 376 IS - 6599 PY - 2022 SN - 0036-8075 ER - TY - JOUR AB - Pathogenic variants in genes that cause dilated cardiomyopathy (DCM) and arrhythmogenic cardiomyopathy (ACM) convey high risks for the development of heart failure through unknown mechanisms. Using single-nucleus RNA sequencing, we characterized the transcriptome of 880,000 nuclei from 18 control and 61 failing, nonischemic human hearts with pathogenic variants in DCM and ACM genes or idiopathic disease. We performed genotype-stratified analyses of the ventricular cell lineages and transcriptional states. The resultant DCM and ACM ventricular cell atlas demonstrated distinct right and left ventricular responses, highlighting genotype-associated pathways, intercellular interactions, and differential gene expression at single-cell resolution. Together, these data illuminate both shared and distinct cellular and molecular architectures of human heart failure and suggest candidate therapeutic targets. AU - Reichart, D.* AU - Lindberg, E.L.* AU - Maatz, H.* AU - Miranda, A.M.A.* AU - Viveiros, A.* AU - Shvetsov, N.* AU - Gärtner, A.* AU - Nadelmann, E.R.* AU - Lee, M.* AU - Kanemaru, K.* AU - Ruiz-Orera, J.* AU - Strohmenger, V.* AU - DeLaughter, D.M.* AU - Patone, G.* AU - Zhang, H.* AU - Woehler, A.* AU - Lippert, C.* AU - Kim, Y.* AU - Adami, E.* AU - Gorham, J.M.* AU - Barnett, S.N.* AU - Brown, K.* AU - Buchan, R.J.* AU - Chowdhury, R.A.* AU - Constantinou, C.* AU - Cranley, J.* AU - Felkin, L.E.* AU - Fox, H.* AU - Ghauri, A.* AU - Gummert, J.* AU - Kanda, M.* AU - Li, R.* AU - Mach, L.* AU - McDonough, B.* AU - Samari, S.* AU - Shahriaran, F. AU - Yapp, C.* AU - Stanasiuk, C.* AU - Theotokis, P.I.* AU - Theis, F.J. AU - van den Bogaerdt, A.* AU - Wakimoto, H.* AU - Ware, J.S.* AU - Worth, C.L.* AU - Barton, P.J.R.* AU - Lee, Y.A.* AU - Teichmann, S.A.* AU - Milting, H.* AU - Noseda, M.* AU - Oudit, G.Y.* AU - Heinig, M. AU - Seidman, J.G.* AU - Hubner, N.* AU - Seidman, C.E.* C1 - 65848 C2 - 52823 TI - Pathogenic variants damage cell composition and single cell transcription in cardiomyopathies. JO - Science VL - 377 IS - 6606 PY - 2022 SN - 0036-8075 ER - TY - JOUR AB - The cilium is an antenna-like organelle that performs numerous cellular functions, including motility, sensing, and signaling. The base of the cilium contains a selective barrier that regulates the entry of large intraflagellar transport (IFT) trains, which carry cargo proteins required for ciliary assembly and maintenance. However, the native architecture of the ciliary base and the process of IFT train assembly remain unresolved. In this work, we used in situ cryo-electron tomography to reveal native structures of the transition zone region and assembling IFT trains at the ciliary base in Chlamydomonas. We combined this direct cellular visualization with ultrastructure expansion microscopy to describe the front-to-back stepwise assembly of IFT trains: IFT-B forms the backbone, onto which bind IFT-A, dynein-1b, and finally kinesin-2 before entry into the cilium AU - van den Hoek, H. AU - Klena, N.* AU - Jordan, M.A.* AU - Viar, G.A.* AU - Righetto, R.D. AU - Schaffer, M.* AU - Erdmann, P.S.* AU - Wan, W.* AU - Geimer, S.* AU - Plitzko, J.M.* AU - Baumeister, W.* AU - Pigino, G.* AU - Hamel, V.* AU - Guichard, P.* AU - Engel, B.D. C1 - 65822 C2 - 52922 SP - 543-548 TI - In situ architecture of the ciliary base reveals the stepwise assembly of intraflagellar transport trains. JO - Science VL - 377 IS - 6605 PY - 2022 SN - 0036-8075 ER - TY - JOUR AB - Characterization of the genetic regulation of proteins is essential for understanding disease etiology and developing therapies. We identified 10,674 genetic associations for 3,892 plasma proteins to create a cis-anchored gene-protein-disease map of 1,859 connections that highlights strong cross-disease biological convergence. This proteo-genomic map provides a framework to 1) connect etiologically related diseases, 2) provide biological context for new or emerging disorders, and 3) integrate different biological domains to establish mechanisms for known gene-disease links. Our results identify proteo-genomic connections within and between diseases and establish the value of cis-protein variants for annotation of likely causal disease genes at GWAS loci, addressing a major barrier for experimental validation and clinical translation of genetic discoveries. AU - Pietzner, M.* AU - Wheeler, E.* AU - Carrasco-Zanini, J.* AU - Cortes, A.* AU - Koprulu, M.* AU - Wörheide, M. AU - Oerton, E.* AU - Cook, J.* AU - Stewart, I.D.* AU - Kerrison, N.D.* AU - Luan, J.* AU - Raffler, J. AU - Arnold, M. AU - Arlt, W.* AU - O'Rahilly, S.* AU - Kastenmüller, G. AU - Gamazon, E.R.* AU - Hingorani, A.D.* AU - Scott, R.A.* AU - Wareham, N.J.* AU - Langenberg, C.* C1 - 63268 C2 - 51307 CY - 1200 New York Ave, Nw, Washington, Dc 20005 Usa TI - Mapping the proteo-genomic convergence of human diseases. JO - Science VL - 374 IS - 6569 PB - Amer Assoc Advancement Science PY - 2021 SN - 0036-8075 ER - TY - JOUR AB - The mammalian heart is derived from multiple cell lineages; however, our understanding of when and how the diverse cardiac cell types arise is limited. We mapped the origin of the embryonic mouse heart at single-cell resolution using a combination of transcriptomic, imaging, and genetic lineage labeling approaches. This provided a transcriptional and anatomic definition of cardiac progenitor types. Furthermore, it revealed a cardiac progenitor pool that is anatomically and transcriptionally distinct from currently known cardiac progenitors. Besides contributing to cardiomyocytes, these cells also represent the earliest progenitor of the epicardium, a source of trophic factors and cells during cardiac development and injury. This study provides detailed insights into the formation of early cardiac cell types, with particular relevance to the development of cell-based cardiac regenerative therapies. AU - Tyser, R.C.V.* AU - Ibarra-Soria, X.* AU - McDole, K.* AU - A Jayaram, S.* AU - Godwin, J.* AU - van den Brand, T.A.H.* AU - Miranda, A.M.A.* AU - Scialdone, A. AU - Keller, P.J.* AU - Marioni, J.C.* AU - Srinivas, S.* C1 - 60946 C2 - 49676 CY - 1200 New York Ave, Nw, Washington, Dc 20005 Usa TI - Characterization of a common progenitor pool of the epicardium and myocardium. JO - Science VL - 371 IS - 6533 PB - Amer Assoc Advancement Science PY - 2021 SN - 0036-8075 ER - TY - JOUR AB - In plants, cell-surface immune receptors sense molecular non-self-signatures. Lipid A of Gram-negative bacterial lipopolysaccharide is considered such a non-self-signature. The receptor kinase LIPOOLIGOSACCHARIDE-SPECIFIC REDUCED ELICITATION (LORE) mediates plant immune responses to Pseudomonas and Xanthomonas but not enterobacterial lipid A or lipopolysaccharide preparations. Here, we demonstrate that synthetic and bacterial lipopolysaccharide-copurified medium-chain 3-hydroxy fatty acid (mc-3-OH-FA) metabolites elicit LORE-dependent immunity. The mc-3-OH-FAs are sensed in a chain length- and hydroxylation-specific manner, with free (R)-3-hydroxydecanoic acid [(R)-3-OH-C10:0] representing the strongest immune elicitor. By contrast, bacterial compounds comprising mc-3-OH-acyl building blocks but devoid of free mc-3-OH-FAs-including lipid A or lipopolysaccharide, rhamnolipids, lipopeptides, and acyl-homoserine-lactones-do not trigger LORE-dependent responses. Hence, plants sense low-complexity bacterial metabolites to trigger immune responses. AU - Kutschera, A.* AU - Dawid, C.* AU - Gisch, N.* AU - Schmid, C.* AU - Raasch, L.* AU - Gerster, T.* AU - Schäffer, M.* AU - Smakowska-Luzan, E.* AU - Belkhadir, Y.* AU - Vlot, A.C. AU - Chandler, C.E.* AU - Schellenberger, R.* AU - Schwudke, D.* AU - Ernst, R.K.* AU - Dorey, S.* AU - Hückelhoven, R.* AU - Hofmann, T.* AU - Ranf, S.* C1 - 55845 C2 - 46599 CY - 1200 New York Ave, Nw, Washington, Dc 20005 Usa SP - 178-181 TI - Bacterial medium-chain 3-hydroxy fatty acid metabolites trigger immunity in Arabidopsis plants. JO - Science VL - 364 IS - 6436 PB - Amer Assoc Advancement Science PY - 2019 SN - 0036-8075 ER - TY - JOUR AB - Translational genomics aims to improve human health by building on discoveries made through genetics research and applying them in the clinical setting. This progress has been made possible by technological advances in genomics and analytics and by the digital revolution. Such advances should enable the development of prognostic markers, tailored interventions, and the design of prophylactic preventive approaches. We are at the cusp of predicting disease risk for some disorders by means of polygenic risk scores integrated with classical epidemiological risk factors. This should lead to better risk stratification and clinical decision-making. A deeper understanding of the link between genome-wide sequence and association with well-characterized phenotypes will empower the development of biomarkers to aid diagnosis, inform disease progression trajectories. and allow better targeting of treatments to those patients most likely to respond. AU - Zeggini, E. AU - Gloyn, A.L.* AU - Barton, A.C.* AU - Wain, L.V.* C1 - 57009 C2 - 47467 CY - 1200 New York Ave, Nw, Washington, Dc 20005 Usa SP - 1409-1413 TI - Translational genomics and precision medicine: Moving from the lab to the clinic. JO - Science VL - 365 IS - 6460 PB - Amer Assoc Advancement Science PY - 2019 SN - 0036-8075 ER - TY - JOUR AB - Flatworms of the species Schmidtea mediterranea are immortal-adult animals contain a large pool of pluripotent stem cells that continuously differentiate into all adult cell types. Therefore, single-cell transcriptome profiling of adult animals should reveal mature and progenitor cells. By combining perturbation experiments, gene expression analysis, a computational method that predicts future cell states from transcriptional changes, and a lineage reconstruction method, we placed all major cell types onto a single lineage tree that connects all cells to a single stem cell compartment. We characterized gene expression changes during differentiation and discovered cell types important for regeneration. Our results demonstrate the importance of single-cell transcriptome analysis for mapping and reconstructing fundamental processes of developmental and regenerative biology at high resolution. AU - Conrad, M. C1 - 53783 C2 - 45027 CY - 1200 New York Ave, Nw, Washington, Dc 20005 Usa SP - S7-S7 TI - Molecular underpinnings controlling ferroptotic cell death. JO - Science VL - 120 PB - Amer Assoc Advancement Science PY - 2018 SN - 0036-8075 ER - TY - JOUR AB - Flatworms of the species Schmidtea mediterranea are immortal-adult animals contain a large pool of pluripotent stem cells that continuously differentiate into all adult cell types. Therefore, single-cell transcriptome profiling of adult animals should reveal mature and progenitor cells. By combining perturbation experiments, gene expression analysis, a computational method that predicts future cell states from transcriptional changes, and a lineage reconstruction method, we placed all major cell types onto a single lineage tree that connects all cells to a single stem cell compartment. We characterized gene expression changes during differentiation and discovered cell types important for regeneration. Our results demonstrate the importance of single-cell transcriptome analysis for mapping and reconstructing fundamental processes of developmental and regenerative biology at high resolution. AU - Dawed, A.Y.* AU - Mari, A.* AU - McDonald, T.J.* AU - Hong, M.-.* AU - Sharma, S. AU - Robertson, N.R.* AU - Mahajan, A.* AU - Walker, M.* AU - Gough, S.C.* AU - Zhou, K.* AU - Forgie, I.* AU - Ruetten, H.* AU - Jones, A.G.* AU - Pearson, E.R.* C1 - 53786 C2 - 45025 CY - 1200 New York Ave, Nw, Washington, Dc 20005 Usa SP - 13-14 TI - GLP-1 receptor variants markedly differentiate glycaemic response to GLP-1 receptor agonists: A direct study. JO - Science VL - 123 PB - Amer Assoc Advancement Science PY - 2018 SN - 0036-8075 ER - TY - JOUR AB - An annotated reference sequence representing the hexaploid bread wheat genome in 21 pseudomolecules has been analyzed to identify the distribution and genomic context of coding and noncoding elements across the A, B, and D subgenomes. With an estimated coverage of 94% of the genome and containing 107,891 high-confidence gene models, this assembly enabled the discovery of tissue-and developmental stage-related coexpression networks by providing a transcriptome atlas representing major stages of wheat development. Dynamics of complex gene families involved in environmental adaptation and end-use quality were revealed at subgenome resolution and contextualized to known agronomic single-gene or quantitative trait loci. This community resource establishes the foundation for accelerating wheat research and application through improved understanding of wheat biology and genomics-assisted breeding. AU - International Wheat Genome Sequencing Consortium (Eversole, K.* AU - Feuillet, C.* AU - Keller, B.* AU - Rogers, J.* AU - Stein, N.* AU - Appels, R.*) AU - Pozniak, C.J.* AU - Choulet, F.* AU - Distelfeld, A. AU - Poland, J.* AU - Ronen, G* AU - Sharpe, A.G.* AU - Pozniak, C.* AU - Barad, O.* AU - Baruch, K.* AU - Choulet, F.* AU - Keeble-Gagnère, G.* AU - Mascher, M.* AU - Ben-Zvi, G.* AU - Josselin, A.A.* AU - Himmelbach, A.* AU - Balfourier, F.* AU - Gutierrez-Gonzalez, J.* AU - Hayden, M.* AU - Josselin, A.A.* AU - Koh, C.* AU - Muehlbauer, G.* AU - Pasam, R.K.* AU - Paux, E.* AU - Rigault, P.* AU - Tibbits, J.* AU - Tiwari, V.* AU - Choulet, F.* AU - Spannagl, M. AU - Lang, D. AU - Gundlach, H. AU - Haberer, G. AU - Mayer, K.F.X. AU - Ormanbekova, D. AU - Paux, E.* AU - Prade, V.M. AU - Šimková, H.* AU - Wicker, T.* AU - Swarbreck, D.* AU - Rimbert, H.* AU - Guilhot, N.* AU - Kaithakottil, G.* AU - Keilwagen, J.* AU - Leroy, P.* AU - Lux, T. AU - Twardziok, S.O. AU - Venturini, L.* AU - Juhász, A* AU - Abrouk, M* AU - Fischer, I.P. AU - Uauy, C.* AU - Borrill, P* AU - Ramirez-Gonzalez, R.H.* AU - Arnaud, D.* AU - Chalabi, S.* AU - Chalhoub, B.* AU - Cory, A.* AU - Datla, R.* AU - Davey, M.W.* AU - Hayden, M.* AU - Jacobs, J.* AU - Robinson, S.J.* AU - Steuernagel, B.* AU - Tibbits, J.* AU - Tiwari, V.* AU - van Ex, F.* AU - Wulff, B.B.H.* AU - Robinson, S.J.* AU - Cory, A.* AU - Benhamed, M.* AU - Paux, E.* AU - Bendahmane, A.* AU - Concia, L.* AU - Latrasse, D.* AU - Rogers, J.* AU - Alaux, M.* AU - Bartoš, J.* AU - Bellec, A.* AU - Berges, H.* AU - Doležel, J.* AU - Frenkel, Z* AU - Gill, B.* AU - Korol, A.* AU - Letellier, T.* AU - Olsen, O.A.* AU - Singh, K.* AU - Valárik, M.* AU - van der Vossen, E.* AU - Vautrin, S.* AU - Weining, S.* AU - Korol, A.* AU - Frenkel, Z.* AU - Fahima, T.* AU - Glikson, V.* AU - Raats, D.* AU - Tiwari, V.* AU - Gill, B.* AU - Paux, E.* AU - Číhalíková, J.* AU - Toegelová, H.* AU - Vrána, J.* AU - Sourdille, P.* AU - Darrier, B.* AU - Barabaschi, D.* AU - Cattivelli, L* AU - Hernandez, P.* AU - Galvez, S.* AU - Budak, H.* AU - Jones, J.D.G.* AU - Witek, K.* AU - Yu, G.* AU - Small, I.* AU - Melonek, J.* AU - Zhou, R.* AU - Juhász, A.* AU - Belova, T.* AU - Kanyuka, K.* AU - King, R.* AU - Nilsen, K.* AU - Walkowiak, S.* AU - Cuthbert, R.* AU - Datla, R.* AU - Knox, R.* AU - Wiebe, K.* AU - Xiang, D.* AU - Rohde, A.* AU - Golds, T.* AU - Čížková, J.* AU - Akpinar, B.A.* AU - Biyiklioglu, S.* AU - Muehlbauer, G.* AU - Gao, L.* AU - Gutierrez-Gonzalez, J.* AU - N'Daiye, A.* AU - Číhalíková, J.* AU - Kubaláková, M.* AU - Šafář, J.* AU - Berges, H.* AU - Bellec, A.* AU - Vautrin, S.* AU - Alaux, M.* AU - Alfama, F.* AU - Adam-Blondon, A.F.* AU - Flores, R.* AU - Guerche, C.* AU - Letellier, T.* AU - Loaec, M.* AU - Quesneville, H.* AU - Condie, J.* AU - Ens, J.* AU - Koh, C.* AU - Maclachlan, R.* AU - Tan, Y.* AU - Paux, E.* AU - Alberti, A.* AU - Aury, J.M.* AU - Barbe, V.* AU - Couloux, A.* AU - Cruaud, C.* AU - Labadie, K.* AU - Mangenot, S.* AU - Wincker, P.* AU - Gill, B.* AU - Kaur, G.* AU - Luo, M.* AU - Sehgal, S.* AU - Chhuneja, P.* AU - Gupta, O.P.* AU - Jindal, S.* AU - Kaur, P.* AU - Malik, P.* AU - Sharma, P.* AU - Yadav, B.* AU - Singh, N.K.* AU - Khurana, J.* AU - Chaudhary, C.* AU - Khurana, P.* AU - Kumar, V.* AU - Mahato, A.* AU - Mathur, S.* AU - Sevanthi, A.* AU - Sharma, N.* AU - Tomar, R.S.* AU - Jacobs, J.* AU - Alaux, M.* AU - Bellec, A.* AU - Berges, H.* AU - Frenkel, Z.* AU - Gill, B.* AU - Korol, A.* AU - van der Vossen, E.* AU - Vautrin, S.* AU - Kaur, G.* AU - Luo, M.* AU - Sehgal, S.* AU - Bartoš, J.* AU - Holušová, K.* AU - Plíhal, O.* AU - Clark, M.D.* AU - Heavens, D.* AU - Kettleborough, G.* AU - Wright, J.* AU - Valárik, M.* AU - Abrouk, M.* AU - Balcárková, B.* AU - Holušová, K.* AU - Hu, Y.* AU - Luo, M.* AU - Salina, E.* AU - Ravin, N.* AU - Skryabin, K.* AU - Beletsky, A.* AU - Kadnikov, V.* AU - Mardanov, A.* AU - Nesterov, M.* AU - Rakitin, A.* AU - Sergeeva, E.* AU - Handa, H.* AU - Kanamori, H.* AU - Katagiri, S.* AU - Kobayashi, F.* AU - Nasuda, S.* AU - Tanaka, T.* AU - Wu, J.* AU - Hayden, M.* AU - Rigault, P.* AU - Cattonaro, F.* AU - Jiumeng, M.* AU - Kugler, K.G. AU - Pfeifer, M. AU - Sandve, S.* AU - Xun, X.* AU - Zhan, B.* AU - Abrouk, M.* AU - Batley, J.* AU - Bayer, P.E.* AU - Edwards, D.* AU - Hayashi, S.* AU - Tulpová, Z.* AU - Visendi, P.* AU - Weining, S.* AU - Cui, L.* AU - Du, X.* AU - Feng, K.* AU - Nie, X.* AU - Tong, W.G.* AU - Wang, L.* AU - Galvez, S.* AU - Lux, T. AU - Ramirez-Gonzalez, R.H.* AU - Venturini, L.* AU - Hernandez, P* AU - Kanyuka, K* AU - Paux, E.* C1 - 54139 C2 - 45275 CY - 1200 New York Ave, Nw, Washington, Dc 20005 Usa TI - Shifting the limits in wheat research and breeding using a fully annotated reference genome. JO - Science VL - 361 IS - 6403 PB - Amer Assoc Advancement Science PY - 2018 SN - 0036-8075 ER - TY - JOUR AB - Flatworms of the species Schmidtea mediterranea are immortal-adult animals contain a large pool of pluripotent stem cells that continuously differentiate into all adult cell types. Therefore, single-cell transcriptome profiling of adult animals should reveal mature and progenitor cells. By combining perturbation experiments, gene expression analysis, a computational method that predicts future cell states from transcriptional changes, and a lineage reconstruction method, we placed all major cell types onto a single lineage tree that connects all cells to a single stem cell compartment. We characterized gene expression changes during differentiation and discovered cell types important for regeneration. Our results demonstrate the importance of single-cell transcriptome analysis for mapping and reconstructing fundamental processes of developmental and regenerative biology at high resolution. AU - Fedoseeva, M. AU - Andreas, N.* AU - Geiselhöringer, A.-L. AU - Garg, G.* AU - de Jong, R.J. AU - Girard, J.P.* AU - Rieman, M.* AU - Schmidt-Weber, C.B. AU - Korn, T.* AU - Weih, F.* AU - Ohnmacht, C.* C1 - 53785 C2 - 45026 CY - 1200 New York Ave, Nw, Washington, Dc 20005 Usa SP - 53-53 TI - The alternative NF kappa B pathway regulates accumulation of tissue Tregs and protects from experimental autoimmune encephalomyelitis. JO - Science VL - 48 PB - Amer Assoc Advancement Science PY - 2018 SN - 0036-8075 ER - TY - JOUR AB - Flatworms of the species Schmidtea mediterranea are immortal-adult animals contain a large pool of pluripotent stem cells that continuously differentiate into all adult cell types. Therefore, single-cell transcriptome profiling of adult animals should reveal mature and progenitor cells. By combining perturbation experiments, gene expression analysis, a computational method that predicts future cell states from transcriptional changes, and a lineage reconstruction method, we placed all major cell types onto a single lineage tree that connects all cells to a single stem cell compartment. We characterized gene expression changes during differentiation and discovered cell types important for regeneration. Our results demonstrate the importance of single-cell transcriptome analysis for mapping and reconstructing fundamental processes of developmental and regenerative biology at high resolution. AU - Frey, K.* AU - Lauffer, F.* AU - Garzorz-Stark, N.* AU - Eyerich, S. AU - Eyerich, K.* C1 - 53795 C2 - 45022 CY - 1200 New York Ave, Nw, Washington, Dc 20005 Usa SP - E23-E23 TI - Mapping of disease severity in patients with systemic sclerosis. JO - Science VL - 27 IS - 3 PB - Amer Assoc Advancement Science PY - 2018 SN - 0036-8075 ER - TY - JOUR AU - Götz, M. C1 - 52961 C2 - 44363 CY - Washington SP - 639-640 TI - Revising concepts about adult stem cells. JO - Science VL - 359 IS - 6376 PB - Amer Assoc Advancement Science PY - 2018 SN - 0036-8075 ER - TY - JOUR AB - The root nodule symbiosis of plants with nitrogen-fixing bacteria impacts global nitrogen cycles and food production but is restricted to a subset of genera within a single clade of flowering plants. To explore the genetic basis for this scattered occurrence, we sequenced the genomes of ten plant species covering the diversity of nodule morphotypes, bacterial symbionts and infection strategies. In a genome-wide comparative analysis of a total of 37 plant species, we discovered signatures of multiple independent loss-of-function events in the indispensable symbiotic regulator NODULE INCEPTION (NIN) in ten out of 13 genomes of non-nodulating species within this clade. The discovery that multiple independent losses shaped the present day distribution of nitrogen-fixing root nodule symbiosis in plants reveals a phylogenetically wider distribution in evolutionary history and a so far underestimated selection pressure against this symbiosis. AU - Griesmann, M. AU - Chang, Y.* AU - Liu, X.* AU - Song, Y.* AU - Haberer, G. AU - Crook, M.B.* AU - Billault-Penneteau, B.* AU - Lauressergues, D.* AU - Keller, J.* AU - Imanishi, L.* AU - Roswanjaya, Y.P.* AU - Kohlen, W.* AU - Pujic, P.* AU - Battenberg, K.* AU - Alloisio, N.* AU - Liang, Y.* AU - Hilhorst, H.* AU - Salgado, M.G.* AU - Hocher, V.* AU - Gherbi, H.* AU - Svistoonoff, S.* AU - Doyle, J.J.* AU - He, S.* AU - Xu, Y.* AU - Xu, S.* AU - Qu, J.* AU - Gao, Q.* AU - Fang, X.* AU - Fu, Y.* AU - Normand, P.* AU - Berry, A.M.* AU - Wall, L.G.* AU - Ané, J.M.* AU - Pawlowski, K.* AU - Xu, X.* AU - Yang, H.* AU - Spannagl, M. AU - Mayer, K.F.X. AU - Wong, G.K.S.* AU - Parniske, M.* AU - Delaux, P.M.* AU - Cheng, S.* C1 - 53849 C2 - 45080 CY - 1200 New York Ave, Nw, Washington, Dc 20005 Usa TI - Phylogenomics reveals multiple losses of nitrogen-fixing root nodule symbiosis. JO - Science VL - 361 IS - 6398 PB - Amer Assoc Advancement Science PY - 2018 SN - 0036-8075 ER - TY - JOUR AU - Hiller, J. AU - Hagl, B. AU - Effner, R. AU - Puel, A.* AU - Schaller, M.* AU - Mascher, B.* AU - Eyerich, S. AU - Eyerich, K.* AU - Jansson, A.F.* AU - Ring, J.J.* AU - Casanova, J.L.* AU - Renner, E.D. AU - Traidl-Hoffmann, C. C1 - 53796 C2 - 45021 CY - 1200 New York Ave, Nw, Washington, Dc 20005 Usa SP - E49-E50 TI - STAT1/STAT3 imbalance determines the clinical phenotype of chronic mucocutaneous candidiasis. JO - Science VL - 27 IS - 3 PB - Amer Assoc Advancement Science PY - 2018 SN - 0036-8075 ER - TY - JOUR AB - Flatworms of the species Schmidtea mediterranea are immortal-adult animals contain a large pool of pluripotent stem cells that continuously differentiate into all adult cell types. Therefore, single-cell transcriptome profiling of adult animals should reveal mature and progenitor cells. By combining perturbation experiments, gene expression analysis, a computational method that predicts future cell states from transcriptional changes, and a lineage reconstruction method, we placed all major cell types onto a single lineage tree that connects all cells to a single stem cell compartment. We characterized gene expression changes during differentiation and discovered cell types important for regeneration. Our results demonstrate the importance of single-cell transcriptome analysis for mapping and reconstructing fundamental processes of developmental and regenerative biology at high resolution. AU - Lauffer, F.* AU - Baghin, V.* AU - Albanesi, C.* AU - Madonna, S.* AU - Steidl, S.* AU - Vandeghinste, N.* AU - Biedermann, T.* AU - Eyerich, S. AU - Eyerich, K.* C1 - 53794 C2 - 45023 CY - 1200 New York Ave, Nw, Washington, Dc 20005 Usa SP - E55-E55 TI - IL-17C: Checkpoint in innate skin immunology. JO - Science VL - 27 IS - 3 PB - Amer Assoc Advancement Science PY - 2018 SN - 0036-8075 ER - TY - JOUR AB - Flatworms of the species Schmidtea mediterranea are immortal-adult animals contain a large pool of pluripotent stem cells that continuously differentiate into all adult cell types. Therefore, single-cell transcriptome profiling of adult animals should reveal mature and progenitor cells. By combining perturbation experiments, gene expression analysis, a computational method that predicts future cell states from transcriptional changes, and a lineage reconstruction method, we placed all major cell types onto a single lineage tree that connects all cells to a single stem cell compartment. We characterized gene expression changes during differentiation and discovered cell types important for regeneration. Our results demonstrate the importance of single-cell transcriptome analysis for mapping and reconstructing fundamental processes of developmental and regenerative biology at high resolution. AU - Plass, M.* AU - Solana, J.* AU - Wolf, F.A. AU - Ayoub, S.* AU - Misios, A.* AU - Glažar, P.* AU - Obermayer, B.* AU - Theis, F.J. AU - Kocks, C.* AU - Rajewsky, N.* C1 - 53439 C2 - 44854 CY - 1200 New York Ave, Nw, Washington, Dc 20005 Usa TI - Cell type atlas and lineage tree of a whole complex animal by single-cell transcriptomics. JO - Science VL - 360 IS - 6391 PB - Amer Assoc Advancement Science PY - 2018 SN - 0036-8075 ER - TY - JOUR AB - The coordinated expression of highly related homoeologous genes in polyploid species underlies the phenotypes of many of the world's major crops. Here we combine extensive gene expression datasets to produce a comprehensive, genome-wide analysis of homoeolog expression patterns in hexaploid bread wheat. Bias in homoeolog expression varies between tissues, with similar to 30% of wheat homoeologs showing nonbalanced expression. We found expression asymmetries along wheat chromosomes, with homoeologs showing the largest inter-tissue, inter-cultivar, and coding sequence variation, most often located in high-recombination distal ends of chromosomes. These transcriptionally dynamic genes potentially represent the first steps toward neo- or subfunctionalization of wheat homoeologs. Coexpression networks reveal extensive coordination of homoeologs throughout development and, alongside a detailed expression atlas, provide a framework to target candidate genes underpinning agronomic traits in wheat. AU - Ramirez-Gonzalez, R.H.* AU - Borrill, P* AU - Lang, D. AU - Harrington, S.A.* AU - Brinton, J.* AU - Venturini, L.* AU - Davey, M.W.* AU - Jacobs, J.* AU - van Ex, F.* AU - Pasha, A.* AU - Khedikar, Y.* AU - Robinson, S.J.* AU - Cory, A.T.* AU - Florio, T.* AU - Concia, L.* AU - Juery, C.* AU - Schoonbeek, H.* AU - Steuernagel, B.* AU - Xiang, D.* AU - Ridout, C.J.* AU - Chalhoub, B.* AU - Mayer, K.F.X. AU - Benhamed, M.* AU - Latrasse, D.* AU - Bendahmane, A.* AU - Wulff, B.B.H.* AU - Appels, R.* AU - Tiwari, V.* AU - Datla, R.* AU - Choulet, F.* AU - Pozniak, C.J.* AU - Provart, N.J.* AU - Sharpe, A.G.* AU - Paux, E.* AU - Spannagl, M. AU - Braeutigam, A.* AU - Uauy, C.* C1 - 54357 C2 - 45485 CY - 1200 New York Ave, Nw, Washington, Dc 20005 Usa TI - The transcriptional landscape of polyploid wheat. JO - Science VL - 361 IS - 6403 PB - Amer Assoc Advancement Science PY - 2018 SN - 0036-8075 ER - TY - JOUR AB - Wheat (Triticum spp.) is one of the founder crops that likely drove the Neolithic transition to sedentary agrarian societies in the Fertile Crescent more than 10,000 years ago. Identifying genetic modifications underlying wheat's domestication requires knowledge about the genome of its allo-tetraploid progenitor, wild emmer (T. turgidum ssp. dicoccoides). We report a 10.1-gigabase assembly of the 14 chromosomes of wild tetraploid wheat, as well as analyses of gene content, genome architecture, and genetic diversity. With this fully assembled polyploid wheat genome, we identified the causal mutations in Brittle Rachis 1 (TtBtr1) genes controlling shattering, a key domestication trait. A study of genomic diversity among wild and domesticated accessions revealed genomic regions bearing the signature of selection under domestication. This reference assembly will serve as a resource for accelerating the genome-assisted improvement of modern wheat varieties. AU - Avni, R.* AU - Nave, M.* AU - Barad, O.* AU - Baruch, K.* AU - Twardziok, S.O. AU - Gundlach, H. AU - Hale, I.* AU - Mascher, M.* AU - Spannagl, M. AU - Wiebe, K.* AU - Jordan, K.W.* AU - Golan, G.* AU - Deek, J.* AU - Ben-Zvi, B.* AU - Ben-Zvi, G.* AU - Himmelbach, A.* AU - MacLachlan, R.P.* AU - Sharpe, A.G.* AU - Fritz, A.* AU - Ben-David, R.* AU - Budak, H.* AU - Fahima, T.* AU - Korol, A.* AU - Faris, J.D.* AU - Hernandez, A.* AU - Mikel, M.A.* AU - Levy, A.A.* AU - Steffenson, B.* AU - Maccaferri, M.* AU - Tuberosa, R.* AU - Cattivelli, L* AU - Faccioli, P.* AU - Ceriotti, A.* AU - Kashkush, K.* AU - Pourkheirandish, M.* AU - Komatsuda, T.* AU - Eilam, T.* AU - Sela, H.* AU - Sharon, A.* AU - Ohad, N.* AU - Chamovitz, D.A.* AU - Mayer, K.F.X. AU - Stein, N.* AU - Ronen, G.M.* AU - Peleg, Z.* AU - Pozniak, C.J.* AU - Akhunov, E.D.* AU - Distelfeld, A.* C1 - 51490 C2 - 43256 CY - Washington SP - 93-97 TI - Wild emmer genome architecture and diversity elucidate wheat evolution and domestication. JO - Science VL - 357 IS - 6346 PB - Amer Assoc Advancement Science PY - 2017 SN - 0036-8075 ER - TY - JOUR AB - The parasitic protists of the Trypanosoma genus infect humans and domestic mammals, causing severe mortality and huge economic losses. The most threatening trypanosomiasis is Chagas disease, affecting up to 12 million people in the Americas. We report a way to selectively kill Trypanosoma by blocking glycosomal/peroxisomal import that depends on the PEX14-PEX5 protein-protein interaction. We developed small molecules that efficiently disrupt the PEX14-PEX5 interaction. This results in mislocalization of glycosomal enzymes, causing metabolic catastrophe, and it kills the parasite. High-resolution x-ray structures and nuclear magnetic resonance data enabled the efficient design of inhibitors with trypanocidal activities comparable to approved medications. These results identify PEX14 as an "Achilles' heel" of the Trypanosoma suitable for the development of new therapies against trypanosomiases and provide the structural basis for their development. AU - Dawidowski, M. AU - Emmanouilidis, L. AU - Kalel, V.C.* AU - Tripsianes, K.* AU - Schorpp, K.K. AU - Hadian, K. AU - Kolonko, M. AU - Erdmann, R.* AU - Sattler, M. AU - Popowicz, G.M. C1 - 50834 C2 - 42540 SP - 1416-1420 TI - Inhibitors of PEX14 disrupt protein import into glycosomes and kill Trypanosoma parasites. JO - Science VL - 355 IS - 6332 PY - 2017 SN - 0036-8075 ER - TY - JOUR AU - Jastroch, M. AU - Tschöp, M.H. C1 - 50760 C2 - 42756 CY - Washington SP - 1124-1125 TI - METABOLISM. Fat controls U. Circulating uridine acts as a hunger signal. JO - Science VL - 355 IS - 6330 PB - Amer Assoc Advancement Science PY - 2017 SN - 0036-8075 ER - TY - JOUR AB - Kinase inhibitors are important cancer therapeutics. Polypharmacology is commonly observed, requiring thorough target deconvolution to understand drug mechanism of action. Using chemical proteomics, we analyzed the target spectrum of 243 clinically evaluated kinase drugs. The data revealed previously unknown targets for established drugs, offered a perspective on the "druggable" kinome, highlighted (non)kinase off-targets, and suggested potential therapeutic applications. Integration of phosphoproteomic data refined drug-affected pathways, identified response markers, and strengthened rationale for combination treatments. We exemplify translational value by discovering SIK2 (salt-inducible kinase 2) inhibitors that modulate cytokine production in primary cells, by identifying drugs against the lung cancer survival marker MELK (maternal embryonic leucine zipper kinase), and by repurposing cabozantinib to treat FLT3-ITD-positive acute myeloid leukemia. This resource, available via the ProteomicsDB database, should facilitate basic, clinical, and drug discovery research and aid clinical decision-making. AU - Klaeger, S.* AU - Heinzlmeir, S.* AU - Wilhelm, M.* AU - Polzer, H.* AU - Vick, B. AU - Koenig, P.A.* AU - Reinecke, M.* AU - Ruprecht, B.* AU - Petzoldt, S.* AU - Meng, C.* AU - Zecha, J.* AU - Reiter, K.* AU - Qiao, H.* AU - Helm, D.* AU - Koch, H.* AU - Schoof, M.* AU - Canevari, G.* AU - Casale, E.* AU - Depaolini, S.R.* AU - Feuchtinger, A. AU - Wu, Z.* AU - Schmidt, T.* AU - Rueckert, L.* AU - Becker, W.* AU - Huenges, J.* AU - Garz, A.K.* AU - Gohlke, B.O.* AU - Zolg, D.P.* AU - Kayser, G.* AU - Vooder, T.* AU - Preissner, R.* AU - Hahne, H.* AU - Tõnisson, N.* AU - Kramer, K.* AU - Götze, K.* AU - Bassermann, F.* AU - Schlegl, J.* AU - Ehrlich, H.C.* AU - Aiche, S.* AU - Walch, A.K. AU - Greif, P.A.* AU - Schneider, S.* AU - Felder, E.R.* AU - Ruland, J.* AU - Médard, G.* AU - Jeremias, I. AU - Spiekermann, K.* AU - Kuster, B.* C1 - 52452 C2 - 43981 CY - Washington TI - The target landscape of clinical kinase drugs. JO - Science VL - 358 IS - 6367 PB - Amer Assoc Advancement Science PY - 2017 SN - 0036-8075 ER - TY - JOUR AB - Dittmar et al. proposed thatmixing alone can explain our observed decrease inmarine dissolved organic sulfur with age. However, their simple model lacks an explanation for the origin of sulfur-depleted organic matter in the deep ocean and cannot adequately reproduce our observed stoichiometric changes. Using radiocarbon age also implicitlymodels the preferential cycling of sulfur that they are disputing. AU - Koch, B.P.* AU - Ksionzek, K.B.* AU - Lechtenfeld, O.J.* AU - McCallister, S.L.* AU - Schmitt-Kopplin, P. AU - Geuer, J.K.* AU - Geibert, W.* C1 - 51255 C2 - 42972 CY - Washington TI - Response to Comment on "Dissolved organic sulfur in the ocean: Biogeochemistry of a petagram inventory". JO - Science VL - 356 IS - 6340 PB - Amer Assoc Advancement Science PY - 2017 SN - 0036-8075 ER - TY - JOUR AB - Although sulfur is an essential element for marine primary production and critical for climate processes, little is known about the oceanic pool of nonvolatile dissolved organic sulfur (DOS). We present a basin-scale distribution of solid-phase extractable DOS in the East Atlantic Ocean and the Atlantic sector of the Southern Ocean. While molar DOS versus dissolved organic nitrogen (DON) ratios of 0.11 ± 0.024 in Atlantic surface water resembled phytoplankton stoichiometry (S/N ~ 0.08), increasing dissolved organic carbon (DOC) versus DOS ratios and decreasing methionine-S yield demonstrated selective DOS removal and active involvement in marine biogeochemical cycles. Based on stoichiometric estimates, the minimum global inventory of marine DOS is 6.7 Pg S, exceeding all other marine organic sulfur reservoirs by an order of magnitude. AU - Ksionzek, K.B.* AU - Lechtenfeld, O.J.* AU - McCallister, S.L.* AU - Schmitt-Kopplin, P. AU - Geuer, J.K.* AU - Geibert, W.* AU - Koch, B.P.* C1 - 49831 C2 - 40968 CY - Washington SP - 456-459 TI - Dissolved organic sulfur in the ocean: Biogeochemistry of a petagram inventory. JO - Science VL - 354 IS - 6311 PB - Amer Assoc Advancement Science PY - 2016 SN - 0036-8075 ER - TY - JOUR AB - Li et al (Research Articles, 28 August 2015, aab3500) purport to present solutions to long-standing challenges in live-cell microscopy, reporting relatively fast acquisition times in conjunction with improved image resolution. We question the methods' reliability to visualize specimen features at sub-100-nanometer scales, because the mandatory mathematical processing of the recorded data leads to artifacts that are either difficult or impossible to disentangle from real features. We are also concerned about the chosen approach of subjectively comparing images from different super-resolution methods, as opposed to using quantitative measures. AU - Sahl, S.J.* AU - Balzarotti, F.* AU - Keller-Findeisen, J.* AU - Leutenegger, M.* AU - Westphal, V.* AU - Egner, A.* AU - Lavoie-Cardinal, F.* AU - Chmyrov, A. AU - Grotjohann, T.* AU - Jakobs, S.* C1 - 48505 C2 - 41112 CY - Washington TI - Comment on "Extended-resolution structured illumination imaging of endocytic and cytoskeletal dynamics". JO - Science VL - 352 IS - 6285 PB - Amer Assoc Advancement Science PY - 2016 SN - 0036-8075 ER - TY - JOUR AB - Scavenger receptor BI (SR-BI) is the major receptor for high-density lipoprotein (HDL) cholesterol (HDL-C). In humans, high amounts of HDL-C in plasma are associated with a lower risk of coronary heart disease (CHD). Mice that have depleted Scarb1 (SR-BI knockout mice) have markedly elevated HDL-C levels but, paradoxically, increased atherosclerosis. The impact of SR-BI on HDL metabolism and CHD risk in humans remains unclear. Through targeted sequencing of coding regions of lipid-modifying genes in 328 individuals with extremely high plasma HDL-C levels, we identified a homozygote for a loss-of-function variant, in which leucine replaces proline 376 (P376L), in SCARB1, the gene encoding SR-BI. The P376L variant impairs posttranslational processing of SR-BI and abrogates selective HDL cholesterol uptake in transfected cells, in hepatocyte-like cells derived from induced pluripotent stem cells from the homozygous subject, and in mice. Large population-based studies revealed that subjects who are heterozygous carriers of the P376L variant have significantly increased levels of plasma HDL-C. P376L carriers have a profound HDL-related phenotype and an increased risk of CHD (odds ratio = 1.79, which is statistically significant). AU - Zanoni, P.* AU - Khetarpal, S.A.* AU - Larach, D.B.* AU - Hancock-Cerutti, W.F.* AU - Millar, J.S.* AU - Cuchel, M.* AU - Derohannessian, S.L.* AU - Kontush, A.* AU - Surendran, P.* AU - Saleheen, D.* AU - Trompet, S.* AU - Jukema, J.W.* AU - de Craen, A.J.* AU - Deloukas, P.* AU - Sattar, N.* AU - Ford, I.* AU - Packard, C.* AU - Al Shafi Majumder, A.* AU - Alam, D.S.* AU - di Angelantonio, E.* AU - Abecasis, G.* AU - Chowdhury, R.* AU - Erdmann, J.* AU - Nørdestgaard, B.G.* AU - Nielsen, S.F.* AU - Tybjærg-Hansen, A.* AU - Schmidt, R.F.* AU - Kuulasmaa, K.* AU - Liu, D.J.* AU - Perola, M.* AU - Blankenberg, S.* AU - Salomaa, V.* AU - Männistö, S.* AU - Amouyel, P.* AU - Arveiler, D.* AU - Ferrieres, J.* AU - Müller-Nurasyid, M. AU - Ferrario, M.* AU - Kee, F.* AU - Willer, C.J.* AU - Samani, N.* AU - Schunkert, H.* AU - Butterworth, A.S.* AU - Howson, J.M.M.* AU - Peloso, G.M.* AU - Stitziel, N.O.* AU - Danesh, J.* AU - Kathiresan, S.* AU - Rader, D.J.* C1 - 48090 C2 - 39896 CY - Washington SP - 1166-1671 TI - Rare variant in scavenger receptor BI raises HDL cholesterol and increases risk of coronary heart disease. JO - Science VL - 351 IS - 6278 PB - Amer Assoc Advancement Science PY - 2016 SN - 0036-8075 ER - TY - JOUR AB - Adult neural stem cells are the source for restoring injured brain tissue. We used repetitive imaging to follow single stem cells in the intact and injured adult zebrafish telencephalon in vivo and found that neurons are generated by both direct conversions of stem cells into postmitotic neurons and via intermediate progenitors amplifying the neuronal output. We observed an imbalance of direct conversion consuming the stem cells and asymmetric and symmetric self-renewing divisions, leading to depletion of stem cells over time. After brain injury, neuronal progenitors are recruited to the injury site. These progenitors are generated by symmetric divisions that deplete the pool of stem cells, a mode of neurogenesis absent in the intact telencephalon. Our analysis revealed changes in the behavior of stem cells underlying generation of additional neurons during regeneration. AU - Barbosa, J.S. AU - Sanchez-Gonzalez, R. AU - di Giaimo, R. AU - Baumgart, E.V. AU - Theis, F.J. AU - Götz, M. AU - Ninkovic, J. C1 - 44873 C2 - 37071 CY - Washington SP - 789-793 TI - Live imaging of adult neural stem cell behavior in the intact and injured zebrafish brain. JO - Science VL - 348 IS - 6236 PB - Amer Assoc Advancement Science PY - 2015 SN - 0036-8075 ER - TY - JOUR AB - Changes to the symbiotic microbiota early in life, or the absence of it, can lead to exacerbated type 2 immunity and allergic inflammations. While it is unclear how the microbiota regulates type 2 immunity, it is a strong inducer of pro-inflammatory T helper (Th) 17 cells and regulatory T cells (Tregs) in the intestine. Here, we report that microbiota-induced Tregs express the nuclear hormone receptor RORγt and differentiate along a pathway that also leads to Th17 cells. In the absence of RORγt(+) Tregs, Th2-driven defense against helminths is more efficient while Th2-associated pathology is exacerbated. Thus, the microbiota regulates type 2 responses through the induction of "type 3" RORγt(+) Tregs and Th17 cells and acts as a key factor in balancing immune responses at mucosal surfaces. AU - Ohnmacht, C. AU - Park, J.H.* AU - Cording, S.* AU - Wing, J.B.* AU - Atarashi, K.* AU - Obata, Y.* AU - Gaboriau-Routhiau, V.* AU - Marques, R.* AU - Dulauroy, S.* AU - Fedoseeva, M. AU - Busslinger, M.* AU - Cerf-Bensussan, N.* AU - Boneca, I.G.* AU - Voehringer, D.* AU - Hase, K.* AU - Honda, K.* AU - Sakaguchi, S.* AU - Eberl, G.* C1 - 46302 C2 - 37490 CY - Washington SP - 989-993 TI - The microbiota regulates type 2 immunity through RORγt+ T cells. JO - Science VL - 349 IS - 6251 PB - Amer Assoc Advancement Science PY - 2015 SN - 0036-8075 ER - TY - JOUR AB - An ordered draft sequence of the 17-gigabase hexaploid bread wheat (Triticum aestivum) genome has been produced by sequencing isolated chromosome arms. We have annotated 124,201 gene loci distributed nearly evenly across the homeologous chromosomes and subgenomes. Comparative gene analysis of wheat subgenomes and extant diploid and tetraploid wheat relatives showed that high sequence similarity and structural conservation are retained, with limited gene loss, after polyploidization. However, across the genomes there was evidence of dynamic gene gain, loss, and duplication since the divergence of the wheat lineages. A high degree of transcriptional autonomy and no global dominance was found for the subgenomes. These insights into the genome biology of a polyploid crop provide a springboard for faster gene isolation, rapid genetic marker development, and precise breeding to meet the needs of increasing food demand worldwide. AU - International Wheat Genome Sequencing Consortium (Appels, R.* AU - Mayer, K.F.X. AU - Rogers, J.* AU - Eversole, K.* AU - Feuillet, C.* AU - Stein, N.* AU - Keller, B.*) AU - Dolezel, J.* AU - Pozniak, C.* AU - Gill, B.* AU - Friebe, B.* AU - Lukaszewski, A.J.* AU - Sourdille, P.* AU - Endo, T.R.* AU - Kubaláková, M.* AU - Cihalikova, J.* AU - Dubska, Z.* AU - Vrana, J.* AU - Sperkova, R.* AU - Šimková, H.* AU - Febrer, M.* AU - Clissold, L.* AU - McLay, K.* AU - Singh, K.* AU - Chhuneja, P.* AU - Singh, N.K.* AU - Khurana, J.P.* AU - Akhunov, E.D.* AU - Choulet, F.* AU - Alberti, A.* AU - Barbe, V.* AU - Wincker, P.* AU - Kanamori, H.* AU - Kobayashi, F.* AU - Itoh, T.* AU - Matsumoto, T.* AU - Sakai, H.* AU - Tanaka, T.* AU - Wu, J.* AU - Ogihara, Y.* AU - Handa, H.* AU - Maclachlan, P.R.* AU - Sharpe, A.* AU - Klassen, D.* AU - Edwards, D.* AU - Batley, J.* AU - Olsen, O.A.* AU - Sandve, S.R.* AU - Lien, S.* AU - Steuernagel, B.* AU - Wulff, B.* AU - Caccamo, M.* AU - Ayling, S.* AU - Ramirez-Gonzalez, R.H.* AU - Clavijo, B.J.* AU - Wright, J.* AU - Pfeifer, M. AU - Spannagl, M. AU - Martis, M.M. AU - Mascher, M.* AU - Chapman, J.* AU - Poland, J.A.* AU - Scholz, U.* AU - Barry, K.* AU - Waugh, R.* AU - Rokhsar, D.S.* AU - Muehlbauer, G.J.* AU - Gundlach, H. AU - Zytnicki, M.* AU - Jamilloux, V.* AU - Quesneville, H.* AU - Wicker, T.* AU - Faccioli, P.* AU - Colaiacovo, M.* AU - Stanca, A.M.* AU - Budak, H.* AU - Cattivelli, L* AU - Glover, N.* AU - Pingault, L.* AU - Paux, E.* AU - Sharma, S. AU - Appels, R.* AU - Bellgard, M.* AU - Chapman, B.* AU - Nussbaumer, T. AU - Bader, K.C. AU - Rimbert, H.* AU - Wang, S.* AU - Knox, R.* AU - Kilian, A.* AU - Alaux, M.* AU - Alfama, F.* AU - Couderc, L.* AU - Guilhot, N.* AU - Viseux, C.* AU - Loaec, M.* AU - Praud, S.* C1 - 32357 C2 - 34995 TI - A chromosome-based draft sequence of the hexaploid bread wheat (Triticum aestivum) genome. JO - Science VL - 345 IS - 6194 PY - 2014 SN - 0036-8075 ER - TY - JOUR AB - We produced a reference sequence of the 1-gigabase chromosome 3B of hexaploid bread wheat. By sequencing 8452 bacterial artificial chromosomes in pools, we assembled a sequence of 774 megabases carrying 5326 protein-coding genes, 1938 pseudogenes, and 85% of transposable elements. The distribution of structural and functional features along the chromosome revealed partitioning correlated with meiotic recombination. Comparative analyses indicated high wheat-specific inter- and intrachromosomal gene duplication activities that are potential sources of variability for adaption. In addition to providing a better understanding of the organization, function, and evolution of a large and polyploid genome, the availability of a high-quality sequence anchored to genetic maps will accelerate the identification of genes underlying important agronomic traits. AU - Choulet, F.* AU - Alberti, A.* AU - Theil, S.* AU - Glover, N.* AU - Barbe, V.* AU - Daron, J.* AU - Pingault, L.* AU - Sourdille, P.* AU - Couloux, A.* AU - Paux, E.* AU - Leroy, P.* AU - Mangenot, S.* AU - Guilhot, N.* AU - Le Gouis, J.* AU - Balfourier, F.* AU - Alaux, M.* AU - Jamilloux, V.* AU - Poulain, J.* AU - Durand, C.* AU - Bellec, A.* AU - Gaspin, C.* AU - Safar, J.* AU - Dolezel, J.* AU - Rogers, J.* AU - Vandepoele, K.* AU - Aury, J.M.* AU - Mayer, K.F.X. AU - Bergès, H.* AU - Quesneville, H.* AU - Wincker, P.* AU - Feuillet, C.* C1 - 31783 C2 - 34765 TI - Structural and functional partitioning of bread wheat chromosome 3B. JO - Science VL - 345 IS - 6194 PY - 2014 SN - 0036-8075 ER - TY - JOUR AU - Eversole, K.* AU - Feuillet, C.* AU - Mayer, K.F.X. AU - Rogers, J.* C1 - 31784 C2 - 34764 CY - Washington SP - 285-287 TI - Slicing the wheat genome. JO - Science VL - 345 IS - 6194 PB - Amer Assoc Advancement Science PY - 2014 SN - 0036-8075 ER - TY - JOUR AB - Current antivirals can control but not eliminate hepatitis-B-virus (HBV), because HBV establishes a stable nuclear cccDNA. Interferon-α treatment can clear HBV but is limited by systemic side effects. Here, we describe how interferon-α can induce specific degradation of the nuclear viral DNA without hepatotoxicity and propose lymphotoxin-β-receptor activation as a therapeutic alternative. Interferon-α and lymphotoxin-β-receptor activation up-regulated APOBEC3A and 3B cytidine-deaminases, respectively, in HBV-infected cells, primary hepatocytes and human liver-needle biopsies. HBV-core protein mediated the interaction with nuclear cccDNA resulting in cytidine-deamination, apurinic/apyrimidinic site formation and finally cccDNA degradation that prevented HBV-reactivation. Genomic DNA was not affected. Thus, inducing nuclear deaminases - e.g., by lymphotoxin-β-receptor activation - allows development of new therapeutics that combined with existing antivirals may cure hepatitis B. AU - Lucifora, J. AU - Xia, Y. AU - Reisinger, F. AU - Zhang, K. AU - Stadler, D. AU - Cheng, X. AU - Sprinzl, M.F. AU - Koppensteiner, H. AU - Makowska, Z.* AU - Volz, T.* AU - Remouchamps, C.* AU - Chou, W.-M. AU - Thasler, W.E.* AU - Hüser, N.* AU - Durantel, D.* AU - Liang, T.J.* AU - Münk, C.* AU - Heim, M.H.* AU - Browning, J.L.* AU - Dejardin, E.* AU - Dandri, M.* AU - Schindler, M. AU - Heikenwälder, M. AU - Protzer, U. C1 - 30615 C2 - 33742 CY - Washington SP - 1221-1228 TI - Specific and nonhepatotoxic degradation of nuclear hepatitis B virus cccDNA. JO - Science VL - 343 IS - 6176 PB - Amer Assoc Advancement Science PY - 2014 SN - 0036-8075 ER - TY - JOUR AB - The allohexaploid bread wheat genome consists of three closely related subgenomes (A, B, and D), but a clear understanding of their phylogenetic history has been lacking. We used genome assemblies of bread wheat and five diploid relatives to analyze genome-wide samples of gene trees, as well as to estimate evolutionary relatedness and divergence times. We show that the A and B genomes diverged from a common ancestor ~7 million years ago and that these genomes gave rise to the D genome through homoploid hybrid speciation 1 to 2 million years later. Our findings imply that the present-day bread wheat genome is a product of multiple rounds of hybrid speciation (homoploid and polyploid) and lay the foundation for a new framework for understanding the wheat genome as a multilevel phylogenetic mosaic. AU - Marcussen, T.* AU - Sandve, S.R.* AU - Heier, L.* AU - Spannagl, M. AU - Pfeifer, M. AU - Jakobsen, K.S.* AU - Wulff, B.B.* AU - Steuernagel, B.* AU - Mayer, K.F.X. AU - Olsen, O.A.* C1 - 31781 C2 - 34767 TI - Ancient hybridizations among the ancestral genomes of bread wheat. JO - Science VL - 345 IS - 6194 PY - 2014 SN - 0036-8075 ER - TY - JOUR AB - Anaerobic microbial degradation of hydrocarbons, typically occurring at the oil-water transition zone, influences the quality of oil reservoirs. In Pitch Lake, Trinidad and Tobago—the world’s largest asphalt lake—we found that microorganisms are metabolically active in minuscule water droplets (1 to 3 microliters) entrapped in oil. Pyrotag sequencing of individual droplet microbiomes revealed complex methanogenic microbial communities actively degrading the oil into a diverse range of metabolites, as shown by nuclear magnetic resonance and Fourier transform ion cyclotron resonance mass spectrometry. High salinity and water-stable isotopes of the droplets indicate a deep subsurface origin. The 13.5% water content and the large surface area of the droplets represent an underestimated potential for biodegradation of oil away from the oil-water transition zone. AU - Meckenstock, R.U. AU - von Netzer, F. AU - Stumpp, C. AU - Lueders, T. AU - Himmelberg, A.M.* AU - Hertkorn, N. AU - Schmitt-Kopplin, P. AU - Harir, M. AU - Hosein, R.* AU - Haque, S.* AU - Schulze-Makuch, D.* C1 - 31902 C2 - 34858 CY - Washington SP - 673-676 TI - Water droplets in oil are microhabitats for microbial life. JO - Science VL - 345 IS - 6197 PB - Amer Assoc Advancement Science PY - 2014 SN - 0036-8075 ER - TY - JOUR AB - Allohexaploid bread wheat (Triticum aestivum L) provides approximately 20% of calories consumed by humans. Lack of genome sequence for the three homeologous and highly similar bread wheat genomes (A, B, and D) has impeded expression analysis of the grain transcriptome. We used previously unknown genome information to analyze the cell type-specific expression of homeologous genes in the developing wheat grain and identified distinct co-expression clusters reflecting the spatiotemporal progression during endosperm development. We observed no global but cell type- and stage-dependent genome dominance, organization of the wheat genome into transcriptionally active chromosomal regions, and asymmetric expression in gene families related to baking quality. Our findings give insight into the transcriptional dynamics and genome interplay among individual grain cell types in a polyploid cereal genome. AU - Pfeifer, M. AU - Kugler, K.G. AU - Sandve, S.R.* AU - Zhan, B.* AU - Rudi, H.* AU - Hvidsten, T.R.* AU - Mayer, K.F.X. AU - Olsen, O.A.* C1 - 31782 C2 - 34766 TI - Genome interplay in the grain transcriptome of hexaploid bread wheat. JO - Science VL - 345 IS - 6194 PY - 2014 SN - 0036-8075 ER - TY - JOUR AB - Fungi play major roles in ecosystem processes, but the determinants of fungal diversity and biogeographic patterns remain poorly understood. Using DNA metabarcoding data from hundreds of globally distributed soil samples, we demonstrate that fungal richness is decoupled from plant diversity. The plant-to-fungus richness ratio declines exponentially toward the poles. Climatic factors, followed by edaphic and spatial variables, constitute the best predictors of fungal richness and community composition at the global scale. Fungi show similar latitudinal diversity gradients to other organisms, with several notable exceptions. These findings advance our understanding of global fungal diversity patterns and permit integration of fungi into a general macroecological framework. AU - Tedersoo, L.* AU - Bahram, M.* AU - Polme, S.* AU - Koljalg, U.* AU - Yorou, N.S.* AU - Wijesundera, R.* AU - Villarreal Ruiz, L.* AU - Vasco-Palacios, A.M.* AU - Thu, P.Q.* AU - Suija, A.* AU - Smith, M.E.* AU - Sharp, C.* AU - Saluveer, E.* AU - Saitta, A.* AU - Rosas, M.* AU - Riit, T.* AU - Ratkowsky, D.* AU - Pritsch, K. AU - Poldmaa, K.* AU - Piepenbring, M.* AU - Phosri, C.* AU - Peterson, M.* AU - Parts, K.* AU - Pärtel, K.* AU - Otsing, E.* AU - Nouhra, E.* AU - Njouonkou, A.L.* AU - Nilsson, R.H.* AU - Morgado, L.N.* AU - Mayor, J.* AU - May, T.W.* AU - Majuakim, L.* AU - Lodge, D.J.* AU - Lee, S.S.* AU - Larsson, K.H.* AU - Kohout, P.* AU - Hosaka, K.* AU - Hiiesalu, I.* AU - Henkel, T.W.* AU - Harend, H.* AU - Guo, L.D.* AU - Greslebin, A.* AU - Grelet, G.* AU - Geml, J.* AU - Gates, G.* AU - Dunstan, W.* AU - Dunk, C.* AU - Drenkhan, R.* AU - Dearnaley, J.* AU - de Kesel, A.* AU - Dang, T.* AU - Chen, X.* AU - Buegger, F. AU - Brearley, F.Q.* AU - Bonito, G.* AU - Anslan, S.* AU - Abell, S.* AU - Abarenkov, K.* C1 - 42856 C2 - 35639 TI - Global diversity and geography of soil fungi. JO - Science VL - 346 IS - 6213 PY - 2014 SN - 0036-8075 ER - TY - JOUR AB - Chisari et al. challenge our central conclusion that the hepatitis B virus (HBV) persistent form, the covalently closed circular DNA (cccDNA), is degraded in a noncytotoxic and specific fashion in the nucleus of infected hepatocytes. Specificity of the assays used, exclusion of cell division or death, and activity of APOBEC3 deaminases in the nucleus, however, were addressed in the paper. AU - Xia, Y. AU - Lucifora, J. AU - Reisinger, F. AU - Heikenwälder, M. AU - Protzer, U. C1 - 31605 C2 - 34726 CY - Washington TI - Response to comment on "Specific and nonhepatotoxic degradation of nuclear hepatitis B virus cccDNA". JO - Science VL - 344 IS - 6189 PB - Amer Assoc Advancement Science PY - 2014 SN - 0036-8075 ER - TY - JOUR AB - A core feature of protective T cell responses to infection is the robust expansion and diversification of naïve antigen-specific T cell populations into short-lived effector and long-lived memory subsets. By in vivo fate mapping, we find a striking variability of immune responses derived from individual CD8+ T cells and show that robust acute and recall immunity requires the initial recruitment of multiple precursors. Unbiased mathematical modeling identifies the random integration of multiple differentiation and division events as the driving force behind this variability. Within this probabilistic framework, cell fate is specified along a linear developmental path that progresses from slowly proliferating long-lived to rapidly expanding short-lived subsets. These data provide insights into how complex biological systems implement stochastic processes to guarantee robust outcomes. AU - Buchholz, V.R.* AU - Flossdorf, M.* AU - Hensel, I.* AU - Kretschmer, L.* AU - Weißbrich, B.* AU - Gräf, P.* AU - Verschoor, A.* AU - Schiemann, M. AU - Höfer, T.* AU - Busch, D.H. C1 - 24029 C2 - 31311 SP - 630-635 TI - Disparate individual fates compose robust CD8+ T cell immunity. JO - Science VL - 340 IS - 6132 PB - Amer. Assoc. Advancement Science PY - 2013 SN - 0036-8075 ER - TY - JOUR AB - The benefits of global pesticide use come at the cost of their widespread occurrence in the environment. An array of abiotic and biotic transformations effectively removes pesticides from the environment, but may give rise to potentially hazardous transformation products. Despite a large body of pesticide degradation data from regulatory testing and decades of pesticide research, it remains difficult to anticipate the extent and pathways of pesticide degradation under specific field conditions. Here, we review the major scientific challenges in doing so and discuss emerging opportunities to identify pesticide degradation processes in the field. AU - Fenner, K.* AU - Canonica, S.* AU - Wackett, L.P.* AU - Elsner, M. C1 - 26745 C2 - 32365 SP - 752-758 TI - Evaluating pesticide degradation in the environment: Blind spots and emerging opportunities. JO - Science VL - 341 IS - 6147 PB - Amer. Soc. Advancement Science PY - 2013 SN - 0036-8075 ER - TY - JOUR AB - Immunoglobulin A (IgA) production at mucosal surfaces contributes to protection against pathogens and controls intestinal microbiota composition. However, mechanisms regulating IgA induction are not completely defined. We show that soluble lymphotoxin α (sLTα3) produced by RORγt(+) innate lymphoid cells (ILCs) controls T cell-dependent IgA induction in the lamina propria via regulation of T cell homing to the gut. By contrast, membrane-bound lymphotoxin β (LTα1β2) produced by RORγt(+) ILCs is critical for T cell-independent IgA induction in the lamina propria via control of dendritic cell functions. Ablation of LTα in RORγt(+) cells abrogated IgA production in the gut and altered microbiota composition. Thus, soluble and membrane-bound lymphotoxins produced by ILCs distinctly organize adaptive immune responses in the gut and control commensal microbiota composition. AU - Kruglov, A.A.* AU - Grivennikov, S.I.* AU - Kuprash, D.V.* AU - Winsauer, C.* AU - Prepens, S.* AU - Seleznik, G.M.* AU - Eberl, G.* AU - Littman, D.R.* AU - Heikenwälder, M. AU - Tumanov, A.V.* AU - Nedospasov, S.A.* C1 - 28619 C2 - 33491 SP - 1243-1246 TI - Nonredundant function of soluble LTα3 produced by innate lymphoid cells in intestinal homeostasis. JO - Science VL - 342 IS - 6163 PB - Amer. Assoc Advancement Science PY - 2013 SN - 0036-8075 ER - TY - JOUR AB - Expansion of a GGGGCC hexanucleotide repeat upstream of the C9orf72 coding region is the most common cause of familial frontotemporal lobar degeneration and amyotrophic lateral sclerosis (FTLD/ALS), but the pathomechanisms involved are unknown. As in other FTLD/ALS variants, characteristic intracellular inclusions of misfolded proteins define C9orf72 pathology, but the core proteins of the majority of inclusions are still unknown. Here, we found that most of these characteristic inclusions contain poly-(Gly-Ala) and, to a lesser extent, poly-(Gly-Pro) and poly-(Gly-Arg) dipeptide-repeat proteins presumably generated by non-ATG-initiated translation from the expanded GGGGCC repeat in three reading frames. These findings directly link the FTLD/ALS-associated genetic mutation to the predominant pathology in patients with C9orf72 hexanucleotide expansion. AU - Mori, K.* AU - Weng, S.M.* AU - Arzberger, T.* AU - May, S.* AU - Rentzsch, K.* AU - Kremmer, E. AU - Schmid, B.* AU - Kretzschmar, H.A.* AU - Cruts, M.* AU - van Broeckhoven, C.* AU - Haass, C.* AU - Edbauer, D.* C1 - 23752 C2 - 31283 SP - 1335-1338 TI - The C9orf72 GGGGCC repeat is translated into aggregating dipeptide-repeat proteins in FTLD/ALS. JO - Science VL - 339 IS - 6125 PB - Amer. Assoc. Advancement Science PY - 2013 SN - 0036-8075 ER - TY - JOUR AB - The asteroid impact near the Russian city of Chelyabinsk on 15 February 2013 was the largest airburst on Earth since the 1908 Tunguska event, causing a natural disaster in an area with a population exceeding one million. Because it occurred in an era with modern consumer electronics, field sensors, and laboratory techniques, unprecedented measurements were made of the impact event and the meteoroid that caused it. Here, we document the account of what happened, as understood now, using comprehensive data obtained from astronomy, planetary science, geophysics, meteorology, meteoritics, and cosmochemistry, and from social science surveys. A good understanding of the Chelyabinsk incident provides a unique opportunity to calibrate the event, with implications for the study of near-Earth objects and developing hazard mitigation strategies for planetary protection. AU - Popova, O.P.* AU - Jenniskens, P.* AU - Emel'yanenko, V.* AU - Kartashova, A.* AU - Biryukov, E.* AU - Khaibrakhmanov, S.* AU - Shuvalov, V.* AU - Rybnov, Y.* AU - Dudorov, A.* AU - Grokhovsky, V.I.* AU - Badyukov, D.D.* AU - Yin, Q.Z.* AU - Gural, P.S.* AU - Albers, J.* AU - Granvik, M.* AU - Evers, L.G.* AU - Kuiper, J.* AU - Kharlamov, V.* AU - Solovyov, A.* AU - Rusakov, Y.S.* AU - Korotkiy, S.* AU - Serdyuk, I.* AU - Korochantsev, A.V.* AU - Larionov, M.Y.* AU - Glazachev, D.* AU - Mayer, A.E.* AU - Gisler, G.* AU - Gladkovsky, S.V.* AU - Wimpenny, J.* AU - Sanborn, M.E.* AU - Yamakawa, A.* AU - Verosub, K.L.* AU - Rowland, D.J.* AU - Roeske, S.* AU - Botto, N.W.* AU - Friedrich, J.M.* AU - Zolensky, M.E.* AU - Le, L.* AU - Ross, D.* AU - Ziegler, K.* AU - Nakamura, T.* AU - Ahn, I.* AU - Lee, J.I.* AU - Zhou, Q.* AU - Li, X.H.* AU - Li, Q.L.* AU - Liu, Y.* AU - Tang, G.Q.* AU - Hiroi, T.* AU - Sears, D.* AU - Weinstein, I.A.* AU - Vokhmintsev, A.S.* AU - Ishchenko, A.V.* AU - Schmitt-Kopplin, P. AU - Hertkorn, N. AU - Nagao, K.* AU - Haba, M.K.* AU - Komatsu, M.* AU - Mikouchi, T.* C1 - 28172 C2 - 32985 SP - 1069-1073 TI - Chelyabinsk airburst, damage assessment, meteorite recovery, and characterization. JO - Science VL - 342 IS - 6162 PB - Amer. Assoc. Advancement Science PY - 2013 SN - 0036-8075 ER - TY - JOUR AB - A genome-wide association study (GWAS) of educational attainment was conducted in a discovery sample of 101,069 individuals and a replication sample of 25,490. Three independent single-nucleotide polymorphisms (SNPs) are genome-wide significant (rs9320913, rs11584700, rs4851266), and all three replicate. Estimated effects sizes are small (coefficient of determination R(2) ≈ 0.02%), approximately 1 month of schooling per allele. A linear polygenic score from all measured SNPs accounts for ≈2% of the variance in both educational attainment and cognitive function. Genes in the region of the loci have previously been associated with health, cognitive, and central nervous system phenotypes, and bioinformatics analyses suggest the involvement of the anterior caudate nucleus. These findings provide promising candidate SNPs for follow-up work, and our effect size estimates can anchor power analyses in social-science genetics. AU - Rietveld, C.A.* AU - Medland, S.E.* AU - Derringer, J.* AU - Yang, J.* AU - Esko, T.* AU - Martin, N.W.* AU - Westra, H.J.* AU - Shakhbazov, K.* AU - Abdellaoui, A.* AU - Agrawal, A.* AU - Albrecht, E. AU - Alizadeh, B.Z.* AU - Amin, N.* AU - Barnard, J.* AU - Baumeister, S.E.* AU - Benke, K.S.* AU - Bielak, L.F.* AU - Boatman, J.A.* AU - Boyle, P.A.* AU - Davies, G.* AU - de Leeuw, C.* AU - Eklund, N.* AU - Evans, D.S.* AU - Ferhmann, R.* AU - Fischer, K.* AU - Gieger, C. AU - Gjessing, H.K.* AU - Hägg, S.* AU - Harris, J.R.* AU - Hayward, C.* AU - Holzapfel, C.* AU - Ibrahim-Verbaas, C.A.* AU - Ingelsson, E.* AU - Jacobsson, B.* AU - Joshi, P.K.* AU - Jugessur, A.* AU - Kaakinen, M.* AU - Kanoni, S.* AU - Karjalainen, J.* AU - Kolcic, I.* AU - Kristiansson, K.* AU - Kutalik, Z.* AU - Lahti, J.* AU - Lee, S.H.* AU - Lin, P.* AU - Lind, P.A.* AU - Liu, Y.* AU - Lohman, K.* AU - Loitfelder, M.* AU - McMahon, G.* AU - Vidal, P.M.* AU - Meirelles, O.* AU - Milani, L.* AU - Myhre, R.* AU - Nuotio, M.L.* AU - Oldmeadow, C.J.* AU - Petrovic, K.E.* AU - Peyrot, W.J.* AU - Polasek, O.* AU - Quaye, L.* AU - Reinmaa, E.* AU - Rice, J.P.* AU - Rizzi, T.S.* AU - Schmidt, H.* AU - Schmidt, R.* AU - Smith, A.V.* AU - Smith, J.A.* AU - Tanaka, T.* AU - Terracciano, A.* AU - van der Loos, M.J.* AU - Vitart, V.* AU - Völzke, H.* AU - Wellmann, J.* AU - Yu, L.* AU - Zhao, W.* AU - Allik, J.* AU - Attia, J.R.* AU - Bandinelli, S.* AU - Bastardot, F.* AU - Beauchamp, J.* AU - Bennett, D.A.* AU - Berger, K.* AU - Bierut, L.J.* AU - Boomsma, D.I.* AU - Bültmann, U.* AU - Campbell, H.* AU - Chabris, C.F.* AU - Cherkas, L.* AU - Chung, M.K.* AU - Cucca, F.* AU - de Andrade, M.* AU - de Jager, P.L.* AU - de Neve, J.E.* AU - Deary, I.J.* AU - Dedoussis, G.V.* AU - Deloukas, P.* AU - Dimitriou, M.* AU - Eiriksdottir, G.* AU - Elderson, M.F.* AU - Eriksson, J.G.* AU - Evans, D.M* AU - Faul, J.D.* AU - Ferrucci, L.* AU - Garcia, M.E.* AU - Grönberg, H.* AU - Guðnason, V.* AU - Hall, P.* AU - Harris, J.M.* AU - Harris, T.B.* AU - Hastie, N.D.* AU - Heath, A.C.* AU - Hernandez, D.G.* AU - Hoffmann, W.* AU - Hofman, A.* AU - Holle, R. AU - Holliday, E.G.* AU - Hottenga, J.J.* AU - Iacono, W.G.* AU - Illig, T. AU - Jarvelin, M.R.* AU - Kähönen, M.* AU - Kaprio, J.* AU - Kirkpatrick, R.M.* AU - Kowgier, M.* AU - Latvala, A.* AU - Launer, L.J.* AU - Lawlor, D.A.* AU - Lehtimäki, T.* AU - Li, J.* AU - Lichtenstein, P.* AU - Lichtner, P. AU - Liewald, D.C.* AU - Madden, P.A.* AU - Magnusson, P.K.* AU - Mäkinen, T.E.* AU - Masala, M.* AU - McGue, M.* AU - Metspalu, A.* AU - Mielck, A. AU - Miller, M.B.* AU - Montgomery, G.W.* AU - Mukherjee, S.* AU - Nyholt, D.R.* AU - Oostra, B.A.* AU - Palmer, L.J.* AU - Palotie, A.* AU - Penninx, B.W.* AU - Perola, M.* AU - Peyser, P.A.* AU - Preisig, M.* AU - Räikkönen, K.* AU - Raitakari, O.T.* AU - Realo, A.* AU - Ring, S.M.* AU - Ripatti, S.* AU - Rivadeneira, F.* AU - Rudan, I.* AU - Rustichini, A.* AU - Salomaa, V.* AU - Sarin, A.P.* AU - Schlessinger, D.* AU - Scott, R.J.* AU - Snieder, H.* AU - St Pourcain, B.* AU - Starr, J.M.* AU - Sul, J.H.* AU - Surakka, I.* AU - Svento, R.* AU - Teumer, A.* AU - The LifeLines Cohort Study* AU - Tiemeier, H.* AU - van Rooij, F.J.* AU - van Wagoner, D.R.* AU - Vartiainen, E.* AU - Viikari, J.* AU - Vollenweider, P.* AU - Vonk, J.M.* AU - Waeber, G.* AU - Weir, D.R.* AU - Wichmann, H.-E. AU - Widen, E.* AU - Willemsen, G.* AU - Wilson, J.F.* AU - Wright, A.F.* AU - Conley, D.* AU - Davey Smith, G.* AU - Franke, L.* AU - Groenen, P.J.* AU - Johannesson, M.* AU - Kardia, S.L.* AU - Krueger, R.F.* AU - Laibson, D.* AU - Martin, N.G.* AU - Meyer, M.N.* AU - Posthuma, D.* AU - Thurik, A.R.* AU - Timpson, N.J.* AU - Uitterlinden, A.G.* AU - van Duijn, C.M.* AU - Visscher, P.M.* AU - Benjamin, D.J.* AU - Cesarini, D.* AU - Koellinger, P.D.* C1 - 24941 C2 - 31727 SP - 1467-1471 TI - GWAS of 126,559 individuals identifies genetic variants associated with educational attainment. JO - Science VL - 340 IS - 6139 PB - Amer. Assoc. Advancement Science PY - 2013 SN - 0036-8075 ER - TY - JOUR AB - Pathogen-associated molecular patterns decisively influence antiviral immune responses, whereas the contribution of endogenous signals of tissue damage, also known as damage-associated molecular patterns or alarmins, remains ill defined. We show that interleukin-33 (IL-33), an alarmin released from necrotic cells, is necessary for potent CD8(+) T cell (CTL) responses to replicating, prototypic RNA and DNA viruses in mice. IL-33 signaled through its receptor on activated CTLs, enhanced clonal expansion in a CTL-intrinsic fashion, determined plurifunctional effector cell differentiation, and was necessary for virus control. Moreover, recombinant IL-33 augmented vaccine-induced CTL responses. Radio-resistant cells of the splenic T cell zone produced IL-33, and efficient CTL responses required IL-33 from radio-resistant cells but not from hematopoietic cells. Thus, alarmin release by radio-resistant cells orchestrates protective antiviral CTL responses. AU - Bonilla, W.V.* AU - Fröhlich, A.* AU - Senn, K.* AU - Kallert, S.* AU - Fernandez, M.* AU - Johnson, S.* AU - Kreutzfeldt, M.* AU - Hegazy, A.N.* AU - Schrick, C.* AU - Fallon, P.G.* AU - Klemenz, R.* AU - Nakae, S.* AU - Adler, H. AU - Merkler, D.* AU - Löhning, M.* AU - Pinschewer, D.D.* C1 - 7225 C2 - 29572 SP - 984-989 TI - The alarmin interleukin-33 drives protective antiviral CD8+ T cell responses. JO - Science VL - 335 IS - 6071 PB - American Assoc. for the Advancement of Science PY - 2012 SN - 0036-8075 ER - TY - JOUR AB - Doppler weather radar imaging enabled the rapid recovery of the Sutter's Mill meteorite after a rare 4-kiloton of TNT-equivalent asteroid impact over the foothills of the Sierra Nevada in northern California. The recovered meteorites survived a record high-speed entry of 28.6 kilometers per second from an orbit close to that of Jupiter-family comets (Tisserand's parameter = 2.8 ± 0.3). Sutter's Mill is a regolith breccia composed of CM (Mighei)-type carbonaceous chondrite and highly reduced xenolithic materials. It exhibits considerable diversity of mineralogy, petrography, and isotope and organic chemistry, resulting from a complex formation history of the parent body surface. That diversity is quickly masked by alteration once in the terrestrial environment but will need to be considered when samples returned by missions to C-class asteroids are interpreted. AU - Jenniskens, P.* AU - Fries, M.D.* AU - Yin, Q.Z.* AU - Zolensky, M.* AU - Krot, A.N.* AU - Sandford, S.A.* AU - Sears, D.* AU - Beauford, R.* AU - Ebel, D.S.* AU - Friedrich, J.M.* AU - Nagashima, K.* AU - Wimpenny, J.* AU - Yamakawa, A.* AU - Nishiizumi, K.* AU - Hamajima, Y.* AU - Caffee, M.W.* AU - Welten, K.C.* AU - Laubenstein, M.* AU - Davis, A.M.* AU - Simon, S.B.* AU - Heck, P.R.* AU - Young, E.D.* AU - Kohl, I.E.* AU - Thiemens, M.H.* AU - Nunn, M.H.* AU - Mikouchi, T.* AU - Hagiya, K.* AU - Ohsumi, K.* AU - Cahill, T.A.* AU - Lawton, J.A.* AU - Barnes, D.* AU - Steele, A.* AU - Rochette, P.* AU - Verosub, K.L.* AU - Gattacceca, J.* AU - Cooper, G.* AU - Glavin, D.P.* AU - Burton, A.S.* AU - Dworkin, J.P.* AU - Elsila, J.E.* AU - Pizzarello, S.* AU - Ogliore, R.* AU - Schmitt-Kopplin, P. AU - Harir, M. AU - Hertkorn, N. AU - Verchovsky, A.* AU - Grady, M.* AU - Nagao, K.* AU - Okazaki, R.* AU - Takechi, H.* AU - Hiroi, T.* AU - Smith, K.* AU - Silber, E.A.* AU - Brown, P.G.* AU - Albers, J.* AU - Klotz, D.* AU - Hankey, M.* AU - Matson, R.* AU - Fries, J.A.* AU - Walker, R.J.* AU - Puchtel, I.* AU - Lee, C.T.* AU - Erdman, M.E.* AU - Eppich, G.R.* AU - Roeske, S.* AU - Gabelica, Z.* AU - Lerche, M.* AU - Nuevo, M.* AU - Girten, B.* AU - Worden, S.P.* C1 - 11686 C2 - 30755 SP - 1583-1587 TI - Radar-enabled recovery of the Sutter's Mill meteorite, a carbonaceous chondrite regolith breccia. JO - Science VL - 338 IS - 6114 PB - American Assoc. of Advancement in Science PY - 2012 SN - 0036-8075 ER - TY - JOUR AB - In different phases of the transcription cycle, RNA polymerase (Pol) II recruits various factors via its C-terminal domain (CTD), which consists of conserved heptapeptide repeats with the sequence Tyr(1)-Ser(2)-Pro(3)-Thr(4)-Ser(5)-Pro(6)-Ser(7). We show that the CTD of transcribing yeast Pol II is phosphorylated at Tyr(1), in addition to Ser(2), Thr(4), Ser(5), and Ser(7). Tyr(1) phosphorylation stimulates binding of elongation factor Spt6 and impairs recruitment of termination factors Nrd1, Pcf11, and Rtt103. Tyr(1) phosphorylation levels rise downstream of the transcription start site and decrease before the polyadenylation site, largely excluding termination factors from gene bodies. These results show that CTD modifications trigger and block factor recruitment and lead to an extended CTD code that explains transcription cycle coordination on the basis of differential phosphorylation of Tyr(1), Ser(2), and Ser(5). AU - Meyer, A.* AU - Heidemann, M. AU - Lidschreiber, M.* AU - Schreieck, A.* AU - Sun, M.* AU - Hintermair, C. AU - Kremmer, E. AU - Eick, D. AU - Cramer, P.* C1 - 7674 C2 - 30143 SP - 1723-1725 TI - CTD tyrosine phosphorylation impairs termination factor recruitment to RNA polymerase II. JO - Science VL - 336 IS - 6089 PB - Amer. Assoc. Advancement Science PY - 2012 SN - 0036-8075 ER - TY - JOUR AB - The impact of glial neurotransmitter receptors in vivo is still elusive. In the cerebellum, Bergmann glial (BG) cells express alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-type glutamate receptors (AMPARs) composed exclusively of GluA1 and/or GluA4 subunits. With the use of conditional gene inactivation, we found that the majority of cerebellar GluA1/A4-type AMPARs are expressed in BG cells. In young mice, deletion of BG AMPARs resulted in retraction of glial appendages from Purkinje cell (PC) synapses, increased amplitude and duration of evoked PC currents, and a delayed formation of glutamatergic synapses. In adult mice, AMPAR inactivation also caused retraction of glial processes. The physiological and structural changes were accompanied by behavioral impairments in fine motor coordination. Thus, BG AMPARs are essential to optimize synaptic integration and cerebellar output function throughout life. AU - Saab, A.S.* AU - Neumeyer, A.* AU - Jahn, H.M.* AU - Cupido, A.* AU - Simek, A.A.M.* AU - Boele, H.J.* AU - Scheller, A.* AU - Le Meur, K.* AU - Götz, M. AU - Monyer, H.* AU - Sprengel, R.* AU - Rubio, M.E.* AU - Deitmer, J.W.* AU - de Zeeuw, C.I.* AU - Kirchhoff, F.* C1 - 8534 C2 - 30212 SP - 749-753 TI - Bergmann glial AMPA receptors are required for fine motor coordination. JO - Science VL - 337 IS - 6095 PB - Amer. Assoc. Advancement Science PY - 2012 SN - 0036-8075 ER - TY - JOUR AB - CENH3 is a centromere-specific histone H3 variant essential for kinetochore assembly. Despite its central role in centromere function, there has been no conclusive evidence supporting CENH3 as sufficient to determine centromere identity. To address this question, we artificially targeted Drosophila CENH3 (CENP-A/CID) as a CID-GFP-LacI fusion protein to stably integrated lac operator (lacO) arrays. This ectopic CID focus assembles a functional kinetochore and directs incorporation of CID molecules without the LacI-anchor, providing evidence for the self-propagation of the epigenetic mark. CID-GFP-LacI-bound extrachromosomal lacO plasmids can assemble kinetochore proteins and bind microtubules, resulting in their stable transmission for several cell generations even after eliminating CID-GFP-LacI. We conclude that CID is both necessary and sufficient to serve as an epigenetic centromere mark and nucleate heritable centromere function. AU - Mendiburo, M.J.* AU - Padeken, J.* AU - Fülöp, S. AU - Schepers, A. AU - Heun, P.* C1 - 6672 C2 - 29089 SP - 686-690 TI - Drosophila CENH3 is sufficient for centromere formation. JO - Science VL - 334 IS - 6056 PB - Amer Assoc Advancement Science PY - 2011 SN - 0036-8075 ER - TY - JOUR AB - The corticotropin-releasing hormone receptor 1 (CRHR1) critically controls behavioral adaptation to stress and is causally linked to emotional disorders. Using neurochemical and genetic tools, we determined that CRHR1 is expressed in forebrain glutamatergic and γ-aminobutyric acid-containing (GABAergic) neurons as well as in midbrain dopaminergic neurons. Via specific CRHR1 deletions in glutamatergic, GABAergic, dopaminergic, and serotonergic cells, we found that the lack of CRHR1 in forebrain glutamatergic circuits reduces anxiety and impairs neurotransmission in the amygdala and hippocampus. Selective deletion of CRHR1 in midbrain dopaminergic neurons increases anxiety-like behavior and reduces dopamine release in the prefrontal cortex. These results define a bidirectional model for the role of CRHR1 in anxiety and suggest that an imbalance between CRHR1-controlled anxiogenic glutamatergic and anxiolytic dopaminergic systems might lead to emotional disorders. AU - Refojo, D.* AU - Schweizer, M.* AU - Kuehne, C.* AU - Ehrenberg, S.* AU - Thoeringer, C.* AU - Vogl, A.M.* AU - Dedic, N.* AU - Schumacher, M.* AU - von Wolff, G.* AU - Avrabos, C.* AU - Touma, C.* AU - Engblom, D.* AU - Schütz, G.* AU - Nave, K.A.* AU - Eder, M.* AU - Wotjak, C.T.* AU - Sillaber, I.* AU - Holsboer, F.* AU - Wurst, W. AU - Deussing, J.M.* C1 - 6729 C2 - 29177 SP - 1903-1907 TI - Glutamatergic and dopaminergic neurons mediate anxiogenic and anxiolytic effects of CRHR1. JO - Science VL - 333 IS - 6051 PB - American Assoc. for the Advancement of Science PY - 2011 SN - 0036-8075 ER - TY - JOUR AB - The carboxy-terminal domain (CTD) of RNA polymerase II (RNAPII) in mammals undergoes extensive posttranslational modification, which is essential for transcriptional initiation and elongation. Here, we show that the CTD of RNAPII is methylated at a single arginine (R1810) by the coactivator-associated arginine methyltransferase 1 (CARM1). Although methylation at R1810 is present on the hyperphosphorylated form of RNAPII in vivo, Ser2 or Ser5 phosphorylation inhibits CARM1 activity toward this site in vitro, suggesting that methylation occurs before transcription initiation. Mutation of R1810 results in the misexpression of a variety of small nuclear RNAs and small nucleolar RNAs, an effect that is also observed in Carm1(-/-) mouse embryo fibroblasts. These results demonstrate that CTD methylation facilitates the expression of select RNAs, perhaps serving to discriminate the RNAPII-associated machinery recruited to distinct gene types. AU - Sims, R.J.* AU - Rojas, L.A.* AU - Beck, D.* AU - Bonasio, R.* AU - Schüller, R. AU - Drury, W.J.* AU - Eick, D. AU - Reinberg, D.* C1 - 5385 C2 - 28488 SP - 99-103 TI - The C-terminal domain of RNA polymerase II is modified by site-specific methylation. JO - Science VL - 332 IS - 6025 PB - Amer Assoc Advancement Science PY - 2011 SN - 0036-8075 ER - TY - JOUR AB - Biotrophic pathogens, such as the related maize pathogenic fungi Ustilago maydis and Sporisorium reilianum, establish an intimate relationship with their hosts by secreting protein effectors. Because secreted effectors interacting with plant proteins should rapidly evolve, we identified variable genomic regions by sequencing the genome of S. reilianum and comparing it with the U. maydis genome. We detected 43 regions of low sequence conservation in otherwise well-conserved syntenic genomes. These regions primarily encode secreted effectors and include previously identified virulence clusters. By deletion analysis in U. maydis, we demonstrate a role in virulence for four previously unknown diversity regions. This highlights the power of comparative genomics of closely related species for identification of virulence determinants. AU - Schirawski, J.* AU - Mannhaupt, G. AU - Münch, K.* AU - Brefort, T.* AU - Schipper, K.* AU - Doehlemann, G.* AU - di Stasio, M.* AU - Rössel, N.* AU - Mendoza-Mendoza, A.* AU - Pester, D.* AU - Müller, O.* AU - Winterberg, B.* AU - Meyer, E.* AU - Ghareeb, H.* AU - Wollenberg, T.* AU - Münsterkötter, M. AU - Wong, P. AU - Walter, M. AU - Stukenbrock, E.* AU - Güldener, U. AU - Kahmann, R.* C1 - 4680 C2 - 28144 SP - 1546-1548 TI - Pathogenicity determinants in smut fungi revealed by genome comparison. JO - Science VL - 330 IS - 6010 PB - American Assoc. for the Advancement of Science PY - 2010 SN - 0036-8075 ER - TY - JOUR AB - Development of powerful, high-throughput technologies, together with globalization of scientific research, presents the biomedical research community with unprecedented challenges for the management, archiving, and distribution of data and bioresources (1). We need a social contract between funding agencies and the scientific community to accommodate “bottom-up” integration and “top-down” financing of databases and biorepositories on an international scale. AU - Schofield, P.N.* AU - Eppig, J.* AU - Huala, E.* AU - Hrabě de Angelis, M. AU - Harvey, M.* AU - Davidson, D.* AU - Weaver, T.* AU - Brown, S.* AU - Smedley, D.* AU - Rosenthal, N.* AU - Schughart, K.* AU - Aidinis, V.* AU - Tocchini-Valentini, G.* AU - Hancock, J.M.* C1 - 22581 C2 - 30036 SP - 592-593 TI - Research funding: Sustaining the data and bioresource commons. JO - Science VL - 330 IS - 6004 PB - Amer. Assoc. Advancement Science PY - 2010 SN - 0036-8075 ER - TY - JOUR AB - Obesity results from chronic energy surplus and excess lipid storage in white adipose tissue (WAT). In contrast, brown adipose tissue (BAT) efficiently burns lipids through adaptive thermogenesis. Studying mouse models, we show that cyclooxygenase (COX)-2, a rate-limiting enzyme in prostaglandin (PG) synthesis, is a downstream effector of beta-adrenergic signaling in WAT and is required for the induction of BAT in WAT depots. PG shifted the differentiation of defined mesenchymal progenitors toward a brown adipocyte phenotype. Overexpression of COX-2 in WAT induced de novo BAT recruitment in WAT, increased systemic energy expenditure, and protected mice against high-fat diet-induced obesity. Thus, COX-2 appears integral to de novo BAT recruitment, which suggests that the PG pathway regulates systemic energy homeostasis. AU - Vegiopoulos, A.* AU - Müller-Decker, K.* AU - Strzoda, D.* AU - Schmitt, I.* AU - Chichelnitskiy, E.* AU - Ostertag, A.* AU - Berriel Diaz, M.* AU - Rozman, J. AU - Hrabě de Angelis, M.* AU - Nüsing, R.M.* AU - Meyer, C.W.* AU - Wahli, W.* AU - Klingenspor, M.* AU - Herzig, S.* C1 - 3214 C2 - 27275 SP - 1158-1161 TI - Cyclooxygenase-2 controls energy homeostasis in mice by de novo recruitment of brown adipocytes. JO - Science VL - 328 IS - 5982 PB - American Assoc. for the Advancement of Science PY - 2010 SN - 0036-8075 ER - TY - JOUR AB - The ability of Anopheles gambiae mosquitoes to transmit Plasmodium parasites is highly variable between individuals. However, the genetic basis of this variability has remained unknown. We combined genome-wide mapping and reciprocal allele-specific RNA interference (rasRNAi) to identify the genomic locus that confers resistance to malaria parasites and demonstrated that polymorphisms in a single gene encoding the antiparasitic thioester-containing protein 1 (TEP1) explain a substantial part of the variability in parasite killing. The link between TEP1 alleles and resistance to malaria may offer new tools for controlling malaria transmission. The successful application of rasRNAi in Anopheles suggests that it could also be applied to other organisms where RNAi is feasible to dissect complex phenotypes to the level of individual quantitative trait alleles. AU - Blandin, S.A.* AU - Wang-Sattler, R. AU - Lamacchia, M.* AU - Gagneur, J.* AU - Lycett, G.* AU - Ning, Y.* AU - Levashina, E.A.* AU - Steinmetz, L.M.* C1 - 1512 C2 - 26485 CY - United States SP - 147-150 TI - Dissecting the genetic basis of resistance to malaria parasites in Anopheles gambiae. JO - Science VL - 326 IS - 5949 PB - Science PY - 2009 SN - 0036-8075 ER - TY - JOUR AB - The constant regeneration of the blood system during hematopoiesis requires tightly controlled lineage decisions of hematopoietic progenitor cells (HPCs). Because of technical limitations, differentiation of individual HPCs could not previously be analyzed continuously. It was therefore disputed whether cell-extrinsic cytokines can instruct HPC lineage choice or only allow survival of cells that are already lineage-restricted. Here, we used bioimaging approaches that allow the continuous long-term observation of individual differentiating mouse HPCs. We demonstrate that the physiological cytokines, macrophage colony-stimulating factor and granulocyte colony-stimulating factor, can instruct hematopoietic lineage choice. AU - Rieger, M. AU - Hoppe, P.S. AU - Smejkal, B.M. AU - Eitelhuber, A.C. AU - Schroeder, T. C1 - 2056 C2 - 26374 SP - 217-218 TI - Hematopoietic cytokines can instruct lineage choice. JO - Science VL - 325 IS - 5937 PB - Amer Assoc Advancement Science PY - 2009 SN - 0036-8075 ER - TY - JOUR AB - Picoeukaryotes are a taxonomically diverse group of organisms less than 2 micrometers in diameter. Photosynthetic marine picoeukaryotes in the genus Micromonas thrive in ecosystems ranging from tropical to polar and could serve as sentinel organisms for biogeochemical fluxes of modern oceans during climate change. These broadly distributed primary producers belong to an anciently diverged sister clade to land plants. Although Micromonas isolates have high 18S ribosomal RNA gene identity, we found that genomes from two isolates shared only 90% of their predicted genes. Their independent evolutionary paths were emphasized by distinct riboswitch arrangements as well as the discovery of intronic repeat elements in one isolate, and in metagenomic data, but not in other genomes. Divergence appears to have been facilitated by selection and acquisition processes that actively shape the repertoire of genes that are mutually exclusive between the two isolates differently than the core genes. Analyses of the Micromonas genomes offer valuable insights into ecological differentiation and the dynamic nature of early plant evolution. AU - Worden, A.Z.* AU - Lee, J.H.* AU - Mock, T.* AU - Rouzé, P.* AU - Simmons, M.P.* AU - Aerts, A.L.* AU - Allen, A.E.* AU - Cuvelier, M.L.* AU - Derelle, E.* AU - Everett, M.V.* AU - Foulon, E.* AU - Grimwood, J.* AU - Gundlach, H. AU - Henrissat, B.* AU - Napoli, C.* AU - McDonald, S.M.* AU - Parker, M.S.* AU - RoM.B.A.uts, S.* AU - Salamov, A.* AU - von Dassow, P.* AU - Badger, J.H.* AU - Coutinho, P.M. AU - Demir, E.* AU - Dubchak, I.* AU - Gentemann, C.* AU - Eikrem, W.* AU - Gready, J.E.* AU - John, U.* AU - Lanier, W.* AU - Lindquist, E.A.* AU - Lucas, S.* AU - Mayer, K.F.X.* AU - Moreau, H.* AU - Not, F.* AU - Otillar, R.* AU - Panaud, O.* AU - Pangilinan, J.* AU - Paulsen, I.* AU - Piegu, B.* AU - Poliakov, A.* AU - Robbens, S.* AU - Schmutz, J.* AU - Toulza, E.* AU - Wyss, T.* AU - Zelensky, A.* AU - Zhou, K.* AU - Armbrust, E.V.* AU - Bhattacharya, D.* AU - Goodenough, U.W.* AU - van de Peer, Y.* AU - Grigoriev, I.V.* C1 - 1461 C2 - 27010 SP - 268-272 TI - Green evolution and dynamic adaptations revealed by genomes of the marine picoeukaryotes Micromonas. JO - Science VL - 324 IS - 5924 PB - Amer Assoc Advancement Science PY - 2009 SN - 0036-8075 ER - TY - JOUR AB - We report the draft genome sequence of the model moss Physcomitrella patens and compare its features with those of flowering plants, from which it is separated by more than 400 million years, and unicellular aquatic algae. This comparison reveals genomic changes concomitant with the evolutionary movement to land, including a general increase in gene family complexity; loss of genes associated with aquatic environments (e.g., flagellar arms); acquisition of genes for tolerating terrestrial stresses (e.g., variation in temperature and water availability); and the development of the auxin and abscisic acid signaling pathways for coordinating multicellular growth and dehydration response. The Physcomitrella genome provides a resource for phylogenetic inferences about gene function and for experimental analysis of plant processes through this plant's unique facility for reverse genetics. AU - Rensing, S.A.* AU - Lang, D.* AU - Zimmer, A.D.* AU - Terry, A.* AU - Salamov, A.* AU - Shapiro, H.* AU - Nishiyama, T.* AU - Perroud, P.F.* AU - Lindquist, E.A.* AU - Kamisugi, Y.* AU - Tanahashi, T.* AU - Sakakibara, K.* AU - Fujita, T.* AU - Oishi, K.* AU - Shin-I, T.* AU - Kuroki, Y.* AU - Toyoda, A.* AU - Suzuki, Y.* AU - Hashimoto, S.* AU - Yamaguchi, K.* AU - Sugano, S.* AU - Kohara, Y.* AU - Fujiyama, A.* AU - Anterola, A.* AU - Aoki, S.* AU - Ashton, N.* AU - Barbazuk, W.B.* AU - Barker, E.* AU - Bennetzen, J.L.* AU - Blankenship, R.* AU - Cho, S.H.* AU - Dutcher, S.K.* AU - Estelle, M.* AU - Fawcett, J.A.* AU - Gundlach, H. AU - Hanada, K.* AU - Heyl, A.* AU - Hicks, K.A.* AU - Hughes, J.* AU - Lohr, M.* AU - Mayer, K.F.X. AU - Melkozernov, A.* AU - Murata, T.* AU - Nelson, D.R.* AU - Pils, B.* AU - Prigge, M.* AU - Reiss, B.* AU - Renner, T.* AU - Rombauts, S.* AU - Rushton, P.J.* AU - Sanderfoot, A.* AU - Schween, G.* AU - Shiu, S.H.* AU - Stueber, K.* AU - Theodoulou, F.L.* AU - Tu, H.* AU - van de Peer, Y.* AU - Verrier, PJ.* AU - Waters, E.* AU - Wood, A.* AU - Yang, L.* AU - Cove, D.* AU - Cuming, AC.* AU - Hasebe, M.* AU - Lucas, S.* AU - Mishler, B.D.* AU - Reski, R.* AU - Grigoriev, I.V.* AU - Quatrano, R.S.* AU - Boore, J.L.* C1 - 1782 C2 - 25510 SP - 64-69 TI - The Physcomitrella genome reveals evolutionary insights into the conquest of land by plants. JO - Science VL - 319 IS - 5859 PB - American Assoc. for the Advancement of Science PY - 2008 SN - 0036-8075 ER - TY - JOUR AB - RNA polymerase II is distinguished by its large carboxyl-terminal repeat domain (CTD), composed of repeats of the consensus heptapeptide Tyr1-Ser2-Pro3-Thr4-Ser5-Pro6-Ser7. Differential phosphorylation of serine-2 and serine-5 at the 5' and 3' regions of genes appears to coordinate the localization of transcription and RNA processing factors to the elongating polymerase complex. Using monoclonal antibodies, we reveal serine-7 phosphorylation on transcribed genes. This position does not appear to be phosphorylated in CTDs of less than 20 consensus repeats. The position of repeats where serine-7 is substituted influenced the appearance of distinct phosphorylated forms, suggesting functional differences between CTD regions. Our results indicate that restriction of serine-7 epitopes to the Linker-proximal region limits CTD phosphorylation patterns and is a requirement for optimal gene expression. AU - Chapman, R.D. AU - Heidemann, M. AU - Albert, T.K. AU - Mailhammer, R. AU - Flatley, A. AU - Meisterernst, M. AU - Kremmer, E. AU - Eick, D. C1 - 1062 C2 - 24979 SP - 1780-1782 TI - Transcribing RNA polymerase II is phosphorylated at CTD residue serine-7. JO - Science VL - 318 IS - 5857 PB - American Assoc. for the Advancement of Science PY - 2007 SN - 0036-8075 ER - TY - JOUR AB - We sequenced and annotated the genome of the filamentous fungus Fusarium graminearum, a major pathogen of cultivated cereals. Very few repetitive sequences were detected, and the process of repeat-induced point mutation, in which duplicated sequences are subject to extensive mutation, may partially account for the reduced repeat content and apparent low number of paralogous (ancestrally duplicated) genes. A second strain of F. graminearum contained more than 10,000 single-nucleotide polymorphisms, which were frequently located near telomeres and within other discrete chromosomal segments. Many highly polymorphic regions contained sets of genes implicated in plant-fungus interactions and were unusually divergent, with higher rates of recombination. These regions of genome innovation may result from selection due to interactions of F. graminearum with its plant hosts. AU - Cuomo, C.A.* AU - Güldener, U. AU - Xu, J.R.* AU - Trail, F.* AU - Turgeon, B.G.* AU - Di, Pietro, A.* AU - Walton, J.D.* AU - Ma, L.J.* AU - Baker, S.E.* AU - Rep, M.* AU - Adam, G.* AU - Antoniw, J.* AU - Baldwin, T.* AU - Calvo, S.* AU - Chang, Y.L.* AU - Decaprio, D.* AU - Gale, L.R.* AU - Gnerre, S.* AU - Goswami, R.S.* AU - Hammond-Kosack, K.* AU - Harris, L.J.* AU - Hilburn, K.* AU - Kennell, JC.* AU - Kroken, S.* AU - Magnuson, J.K.* AU - Mannhaupt, G. AU - Mauceli, E.* AU - Mewes, H.-W. AU - Mitterbauer, R.* AU - Muehlbauer, G.* AU - Münsterkötter, M. AU - Nelson, D.* AU - O'Donnell, K.* AU - Ouellet, T.* AU - Qi, W.* AU - Quesneville, H.* AU - Roncero, M.I.* AU - Seong, K.Y.* AU - Tetko, I.V. AU - Urban, M.* AU - Waalwijk, C.* AU - Ward, T.J.* AU - Yao, J.* AU - Birren, B.W.* AU - Kistler, H.C.* C1 - 4266 C2 - 24569 SP - 1400-1402 TI - The Fusarium graminearum genome reveals a link between localized polymorphism and pathogen specialization. JO - Science VL - 317 IS - 5843 PB - American Assoc. for the Advancement of Science PY - 2007 SN - 0036-8075 ER - TY - JOUR AB - RNA polymerase II (Pol II) transcribes genes that encode proteins and noncoding small nuclear RNAs (snRNAs). The carboxyl-terminal repeat domain (CTD) of the largest subunit of mammalian RNA Pol II, comprising tandem repeats of the heptapeptide consensus Tyr1-Ser2-Pro3-Thr4-Ser5-Pro6-Ser7, is required for expression of both gene types. We show that mutation of serine-7 to alanine causes a specific defect in snRNA gene expression. We also present evidence that phosphorylation of serine-7 facilitates interaction with the snRNA gene-specific Integrator complex. These findings assign a biological function to this amino acid and highlight a gene type-specific requirement for a residue within the CTD heptapeptide, supporting the existence of a CTD code. AU - Egloff, S.* AU - O'Reilly, D.* AU - Chapman, R.D. AU - Taylor, A.* AU - Tanzhaus, K.* AU - Pitts, L.* AU - Eick, D. AU - Murphy, S.* C1 - 1822 C2 - 24980 SP - 1777-1779 TI - Serine-7 of the RNA polymerase II CTD is specifically required for snRNA gene expression. JO - Science VL - 318 IS - 5857 PB - American Assoc. for the Advancement of Science PY - 2007 SN - 0036-8075 ER - TY - JOUR AB - Identification of genetic variants affecting complex traits such as obesity is confounded by many types of bias, especially when effect sizes are small. Given our findings of a positive association between rs7566605 and body mass index in four out of five separate samples, a false positive finding cannot be ruled out with certainty but seems unlikely. Meta-analyses of multiple large studies will help refine the estimate of the effects of rs7566605 on body mass index. AU - Herbert, A.* AU - Gerry, N.P.* AU - McQueen, M.B.* AU - Heid, I.M. AU - Pfeufer, A. AU - Illig, T. AU - Wichmann, H.-E. AU - Meitinger, T. AU - Hunter, D.* AU - Hu, F.B.* AU - Colditz, G.* AU - Hinney, A.* AU - Hebebrand, J.* AU - Koberwitz, K. AU - Zhu, X.F.* AU - Cooper, R.* AU - Ardlie, K.* AU - Lyon, H.* AU - Hirschhorn, J.N.* AU - Laird, N.M.* AU - Lenburg, M.E.* AU - Lange, C.* AU - Christman, M.F.* C1 - 4140 C2 - 24510 SP - 187e TI - Response to Comments on "A Common Genetic Variant Is Associated with Adult and Childhood Obesity". JO - Science VL - 315 IS - 5809 PB - American Assoc. for the Advancement of Science PY - 2007 SN - 0036-8075 ER - TY - JOUR AB - Obesity is a heritable trait and a risk factor for many common diseases such as type 2 diabetes, heart disease, and hypertension. We used a dense whole-genome scan of DNA samples from the Framingham Heart Study participants to identify a common genetic variant near the INSIG2 gene associated with obesity. We have replicated the finding in four separate samples composed of individuals of Western European ancestry, African Americans, and children. The obesity-predisposing genotype is present in 10% of individuals. Our study suggests that common genetic polymorphisms are important determinants of obesity. AU - Herbert, A.* AU - Gerry, N.P.* AU - McQueen, M.B.* AU - Heid, I.M. AU - Pfeufer, A. AU - Illig, T. AU - Wichmann, H.-E. AU - Meitinger, T. AU - Hunter, D.* AU - Hu, F.B.* AU - Colditz, G.* AU - Hinney, A.* AU - Hebebrand, J.* AU - Koberwitz, K.* AU - Zhu, X.* AU - Cooper, R.* AU - Ardlie, K.* AU - Lyon, H.* AU - Hirschhorn, J.N.* AU - Laird, N.M.* AU - Lenburg, M.E.* AU - Lange, C.* AU - Christman, M.F.* C1 - 5227 C2 - 23622 SP - 279-283 TI - A common genetic variant is associated with adult and childhood obesity. JO - Science VL - 312 IS - 5771 PY - 2006 SN - 0036-8075 ER - TY - JOUR AU - Horn, M.* AU - Frishman, D. AU - Rattei, T. AU - Mewes, H.-W. C1 - 4104 C2 - 22396 SP - 728-730 TI - Illuminating the evolutionary history of chlamydiae. JO - Science VL - 304 PY - 2004 SN - 0036-8075 ER - TY - JOUR AU - Hafezparast, M.* AU - Klocke, R.* AU - Ruhrberg, C.* AU - Marquart, A.* AU - Ahmad-Annuar, A.* AU - Bowen, S.* AU - Lalli, G.* AU - Witherden, A.S.* AU - Hummerich, H.* AU - Nicholson, S.* AU - Morgan, P.J.* AU - Oozageer, R.* AU - Priestley, J.V.* AU - Hrabě de Angelis, M. C1 - 22273 C2 - 21046 SP - 808-812 TI - Mutations in Dynein Link Motor Neuron Degeneration to Defects in Retrograde Transport. JO - Science VL - 300 PY - 2003 SN - 0036-8075 ER - TY - JOUR AB - A practical, inexpensive, green chemical process for degrading environmental pollutants is greatly needed, especially for persistent chlorinated pollutants. Here we describe the activation of hydrogen peroxide by tetraamidomacrocylic ligand (TAML) iron catalysts, to destroy the priority pollutants pentachlorophenol (PCP) and 2,4,6-trichlorophenol (TCP). In water, in minutes, under ambient conditions of temperature and pressure, PCP and TCP are completely destroyed at catalyst:substrate ratios of 1:715 and 1:2000, respectively. The fate of about 90% of the carbon and about 99% of the chlorine has been determined in each case. Neither dioxins nor any other toxic compounds are detectable products, and the catalysts themselves show Low toxicity. AU - Gupta, S.S.* AU - Stadler, M.* AU - Noser, Ch.A.* AU - Ghosh, A.* AU - Steinhoff, B.* AU - Lenoir, D. AU - Horwitz, C.P.* AU - Schramm, K.-W. AU - Collins, T.J.* C1 - 9863 C2 - 20148 SP - 326-328 TI - Rapid Total Destruction of Chlorophenols by Activated Hydrogen Peroxide. JO - Science VL - 296 PB - Science PY - 2002 SN - 0036-8075 ER - TY - JOUR AU - Meisterernst, M. C1 - 9864 C2 - 20435 SP - 984-985 TI - Mediator Meets Morpheus. JO - Science VL - 295 PB - American Assoc. for the Advancement of Science PY - 2002 SN - 0036-8075 ER - TY - JOUR AU - Sillaber, I.* AU - Rammes, G.* AU - Zimmermann, S.* AU - Mahal, B.* AU - Zieglgänsberger, W.* AU - Wurst, W. AU - Holboer, F.* AU - Spanagel, R.* C1 - 9865 C2 - 20771 SP - 931-933 TI - Enhanced and delayed stress-induced alcohol drinking in mice lacking functional CRH1 recepors. JO - Science VL - 296 PY - 2002 SN - 0036-8075 ER - TY - JOUR AU - Nadeau, J.H.* AU - Balling, R.* AU - Barsh, G.* AU - Beier, D.* AU - Brown, S.D.* AU - Bucan, M.* AU - Camper, S.* AU - Carlson, G.* AU - Copeland, N.* AU - Eppig, J.* AU - Fletcher, C.* AU - Frankel, W.N.* AU - Ganten, D.* AU - Goldowitz, D.* AU - Goodnow, C.* AU - Guenet, J.L.* AU - Hicks, G.* AU - Hrabě de Angelis, M. AU - Jackson, I.* AU - Jacob, H.J.* AU - Jenkins, N.* AU - Johnson, D.* AU - Justice, M.* AU - Kay, S.* AU - Kingsley, D.* AU - Lehrach, H.* AU - Magnuson, T.* AU - Meisler, M.* AU - Poustka, A.* AU - Rinchik, E.M.* AU - Rossant, J.* AU - Russell, L.B.* AU - Schimenti, J.* AU - Shiroishi, T.* AU - Skarnes, W.C.* AU - Soriano, P.* AU - Stanford, W.* AU - Takahashi, J.S.* AU - Wurst, W.* AU - Zimmer, A.* AU - International Mouse Mutagenesis Consortium (*) C1 - 22703 C2 - 31109 SP - 1251-1255 TI - Sequence interpretation. Functional annotation of mouse genome sequences. JO - Science VL - 291 IS - 5507 PB - Amer. Assoc. Advancement Science PY - 2001 SN - 0036-8075 ER - TY - JOUR AB - The cellular proto-oncogene c-myc is involved in cell proliferation and transformation but is also implicated in the induction of programmed cell death (apoptosis). The same characteristics have been described for the tumor suppressor gene p53, the most commonly mutated gene in human cancer. In quiescent mouse fibroblasts expressing wildtype p53 protein, activation of c-Myc was found to induce apoptosis and cell cycle reentry, preceded by stabilization of p53. In contrast, in quiescent p53-null fibroblasts, activation of c-Myc induced cell cycle reentry but not apoptosis. These results suggest that p53 mediates apoptosis as a safeguard mechanism to prevent cell proliferation induced by oncogene activation. AU - Hermeking, H. AU - Eick, D. C1 - 40018 C2 - 38059 SP - 2091-2093 TI - Mediation of c-myc-induced apoptosis by p53. JO - Science VL - 265 IS - 5181 PY - 1994 SN - 0036-8075 ER - TY - JOUR AB - The participation of (6R) 5,6,7,8-tetrahydrobiopterin (6-BH4) in regulating the tyrosine supply for melanin biosynthesis was investigated by the examination of human keratinocytes, melanocytes, and epidermal suction blisters from normal human skin and from patients with the depigmentation disorder vitiligo. Cells, as well as total epidermis, contained high phenylalanine hydroxylase activities and also displayed the capacity to synthesize and recycle 6-BH4, the essential cofactor for this enzyme in vitiligo, 4a-hydroxy-BH4 dehydratase activity was extremely low or absent, yielding an accumulation of the nonenzymatic by-product 7-tetrahydrobiopterin (7-BH4) at concentrations up to 8 x 10-6 M in the epidermis. This by- product is a potent competitive inhibitor in the phenylalanine hydroxylase reaction with an inhibition constant of 10-6 M. Thus, 6-BH4 seems to control melanin biosynthesis in the human epidermis, whereas 7-BH4 may initiate depigmentation in patients with vitiligo. AU - Schallreuter, K.U.* AU - Wood, J.M.* AU - Pittelkow, M.R.* AU - Gütlich, M. AU - Lemke, K.R.* AU - Rödl, W. AU - Swanson, N.N.* AU - Hitzemann, K.* AU - Ziegler, I. C1 - 40052 C2 - 38074 SP - 1444-1446 TI - Regulation of melanin biosynthesis in the human epidermis by tetrahydrobiopterin. JO - Science VL - 263 IS - 5152 PY - 1994 SN - 0036-8075 ER -