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https://www.readbyqxmd.com/read/27916275/artemisinins-target-gabaa-receptor-signaling-and-impair-%C3%AE-cell-identity
#1
Jin Li, Tamara Casteels, Thomas Frogne, Camilla Ingvorsen, Christian Honoré, Monica Courtney, Kilian V M Huber, Nicole Schmitner, Robin A Kimmel, Roman A Romanov, Caterina Sturtzel, Charles-Hugues Lardeau, Johanna Klughammer, Matthias Farlik, Sara Sdelci, Andhira Vieira, Fabio Avolio, François Briand, Igor Baburin, Peter Májek, Florian M Pauler, Thomas Penz, Alexey Stukalov, Manuela Gridling, Katja Parapatics, Charlotte Barbieux, Ekaterine Berishvili, Andreas Spittler, Jacques Colinge, Keiryn L Bennett, Steffen Hering, Thierry Sulpice, Christoph Bock, Martin Distel, Tibor Harkany, Dirk Meyer, Giulio Superti-Furga, Patrick Collombat, Jacob Hecksher-Sørensen, Stefan Kubicek
Type 1 diabetes is characterized by the destruction of pancreatic β cells, and generating new insulin-producing cells from other cell types is a major aim of regenerative medicine. One promising approach is transdifferentiation of developmentally related pancreatic cell types, including glucagon-producing α cells. In a genetic model, loss of the master regulatory transcription factor Arx is sufficient to induce the conversion of α cells to functional β-like cells. Here, we identify artemisinins as small molecules that functionally repress Arx by causing its translocation to the cytoplasm...
November 30, 2016: Cell
https://www.readbyqxmd.com/read/27916276/a-surveillance-mechanism-ensures-repair-of-dna-lesions-during-zygotic-reprogramming
#2
Sabrina Ladstätter, Kikuë Tachibana-Konwalski
Sexual reproduction culminates in a totipotent zygote with the potential to produce a whole organism. Sperm chromatin reorganization and epigenetic reprogramming that alter DNA and histone modifications generate a totipotent embryo. Active DNA demethylation of the paternal genome has been proposed to involve base excision and DNA repair-based mechanisms. The nature and consequence of DNA lesions generated during reprogramming are not known. Using mouse genetics and chemical biology, we discovered that Tet3-dependent zygotic reprogramming generates paternal DNA lesions that are monitored by a surveillance mechanism...
November 21, 2016: Cell
https://www.readbyqxmd.com/read/27916274/long-term-gaba-administration-induces-alpha-cell-mediated-beta-like-cell-neogenesis
#3
Nouha Ben-Othman, Andhira Vieira, Monica Courtney, Fabien Record, Elisabet Gjernes, Fabio Avolio, Biljana Hadzic, Noémie Druelle, Tiziana Napolitano, Sergi Navarro-Sanz, Serena Silvano, Keith Al-Hasani, Anja Pfeifer, Sandra Lacas-Gervais, Gunter Leuckx, Laura Marroquí, Julien Thévenet, Ole Dragsbaek Madsen, Decio Laks Eizirik, Harry Heimberg, Julie Kerr-Conte, François Pattou, Ahmed Mansouri, Patrick Collombat
The recent discovery that genetically modified α cells can regenerate and convert into β-like cells in vivo holds great promise for diabetes research. However, to eventually translate these findings to human, it is crucial to discover compounds with similar activities. Herein, we report the identification of GABA as an inducer of α-to-β-like cell conversion in vivo. This conversion induces α cell replacement mechanisms through the mobilization of duct-lining precursor cells that adopt an α cell identity prior to being converted into β-like cells, solely upon sustained GABA exposure...
November 18, 2016: Cell
https://www.readbyqxmd.com/read/27866654/crispr-based-technologies-for-the-manipulation-of-eukaryotic-genomes
#4
REVIEW
Alexis C Komor, Ahmed H Badran, David R Liu
The CRISPR-Cas9 RNA-guided DNA endonuclease has contributed to an explosion of advances in the life sciences that have grown from the ability to edit genomes within living cells. In this Review, we summarize CRISPR-based technologies that enable mammalian genome editing and their various applications. We describe recent developments that extend the generality, DNA specificity, product selectivity, and fundamental capabilities of natural CRISPR systems, and we highlight some of the remarkable advancements in basic research, biotechnology, and therapeutics science that these developments have facilitated...
November 15, 2016: Cell
https://www.readbyqxmd.com/read/27773482/regulatory-t-cell-specificity-directs-tolerance-versus-allergy-against-aeroantigens-in-humans
#5
Petra Bacher, Frederik Heinrich, Ulrik Stervbo, Mikalai Nienen, Marco Vahldieck, Christina Iwert, Katrin Vogt, Jutta Kollet, Nina Babel, Birgit Sawitzki, Carsten Schwarz, Stefan Bereswill, Markus M Heimesaat, Guido Heine, Gabriele Gadermaier, Claudia Asam, Mario Assenmacher, Olaf Kniemeyer, Axel A Brakhage, Fátima Ferreira, Michael Wallner, Margitta Worm, Alexander Scheffold
FOXP3+ regulatory T cells (Tregs) maintain tolerance against self-antigens and innocuous environmental antigens. However, it is still unknown whether Treg-mediated tolerance is antigen specific and how Treg specificity contributes to the selective loss of tolerance, as observed in human immunopathologies such as allergies. Here, we used antigen-reactive T cell enrichment to identify antigen-specific human Tregs. We demonstrate dominant Treg-mediated tolerance against particulate aeroallergens, such as pollen, house dust mites, and fungal spores...
October 18, 2016: Cell
https://www.readbyqxmd.com/read/27773481/distinct-hippocampal-pathways-mediate-dissociable-roles-of-context-in-memory-retrieval
#6
Chun Xu, Sabine Krabbe, Jan Gründemann, Paolo Botta, Jonathan P Fadok, Fumitaka Osakada, Dieter Saur, Benjamin F Grewe, Mark J Schnitzer, Edward M Callaway, Andreas Lüthi
Memories about sensory experiences are tightly linked to the context in which they were formed. Memory contextualization is fundamental for the selection of appropriate behavioral reactions needed for survival, yet the underlying neuronal circuits are poorly understood. By combining trans-synaptic viral tracing and optogenetic manipulation, we found that the ventral hippocampus (vHC) and the amygdala, two key brain structures encoding context and emotional experiences, interact via multiple parallel pathways...
October 18, 2016: Cell
https://www.readbyqxmd.com/read/27912066/cell-type-specific-optical-recording-of-membrane-voltage-dynamics-in-freely-moving-mice
#7
Jesse D Marshall, Jin Zhong Li, Yanping Zhang, Yiyang Gong, François St-Pierre, Michael Z Lin, Mark J Schnitzer
Electrophysiological field potential dynamics are of fundamental interest in basic and clinical neuroscience, but how specific cell types shape these dynamics in the live brain is poorly understood. To empower mechanistic studies, we created an optical technique, TEMPO, that records the aggregate trans-membrane voltage dynamics of genetically specified neurons in freely behaving mice. TEMPO has >10-fold greater sensitivity than prior fiber-optic techniques and attains the noise minimum set by quantum mechanical photon shot noise...
December 1, 2016: Cell
https://www.readbyqxmd.com/read/27912065/phosphoribosylation-of-ubiquitin-promotes-serine-ubiquitination-and-impairs-conventional-ubiquitination
#8
Sagar Bhogaraju, Sissy Kalayil, Yaobin Liu, Florian Bonn, Thomas Colby, Ivan Matic, Ivan Dikic
Conventional ubiquitination involves the ATP-dependent formation of amide bonds between the ubiquitin C terminus and primary amines in substrate proteins. Recently, SdeA, an effector protein of pathogenic Legionella pneumophila, was shown to mediate NAD-dependent and ATP-independent ubiquitin transfer to host proteins. Here, we identify a phosphodiesterase domain in SdeA that efficiently catalyzes phosphoribosylation of ubiquitin on a specific arginine via an ADP-ribose-ubiquitin intermediate. SdeA also catalyzes a chemically and structurally distinct type of substrate ubiquitination by conjugating phosphoribosylated ubiquitin to serine residues of protein substrates via a phosphodiester bond...
December 1, 2016: Cell
https://www.readbyqxmd.com/read/27912064/modular-assembly-of-the-bacterial-large-ribosomal-subunit
#9
Joseph H Davis, Yong Zi Tan, Bridget Carragher, Clinton S Potter, Dmitry Lyumkis, James R Williamson
The ribosome is a complex macromolecular machine and serves as an ideal system for understanding biological macromolecular assembly. Direct observation of ribosome assembly in vivo is difficult, as few intermediates have been isolated and thoroughly characterized. Herein, we deploy a genetic system to starve cells of an essential ribosomal protein, which results in the accumulation of assembly intermediates that are competent for maturation. Quantitative mass spectrometry and single-particle cryo-electron microscopy reveal 13 distinct intermediates, which were each resolved to ∼4-5 Å resolution and could be placed in an assembly pathway...
December 1, 2016: Cell
https://www.readbyqxmd.com/read/27912063/structure-of-mammalian-respiratory-supercomplex-i1iii2iv1
#10
Meng Wu, Jinke Gu, Runyu Guo, Yushen Huang, Maojun Yang
The mammalian respiratory chain complexes assemble into supercomplexes (SCs) and reside in the inner mitochondrial membrane to transfer electrons and establish the proton gradient for complex V to synthesize ATP. The precise arrangement of SCs is largely unknown. Here, we report a 4.0-Å cryo-electron microscopy (cryo-EM) structure of the major SC in porcine heart, the 1.7-MDa SCI1III2IV1. The complex III (CIII) dimer and complex IV (CIV) bind at the same side of the L-shaped complex I (CI). Several accessory or supernumerary subunits of CI, such as NDUFA11, NDUFB4, NDUFB8, and NDUFB9, directly contribute to the oligomerization of CI, CIII, and CIV...
December 1, 2016: Cell
https://www.readbyqxmd.com/read/27912062/atomic-structure-of-the-cystic-fibrosis-transmembrane-conductance-regulator
#11
Zhe Zhang, Jue Chen
The cystic fibrosis transmembrane conductance regulator (CFTR) is an anion channel evolved from the ATP-binding cassette (ABC) transporter family. In this study, we determined the structure of zebrafish CFTR in the absence of ATP by electron cryo-microscopy to 3.7 Å resolution. Human and zebrafish CFTR share 55% sequence identity, and 42 of the 46 cystic-fibrosis-causing missense mutational sites are identical. In CFTR, we observe a large anion conduction pathway lined by numerous positively charged residues...
December 1, 2016: Cell
https://www.readbyqxmd.com/read/27912061/tumor-interferon-signaling-regulates-a-multigenic-resistance-program-to-immune-checkpoint-blockade
#12
Joseph L Benci, Bihui Xu, Yu Qiu, Tony J Wu, Hannah Dada, Christina Twyman-Saint Victor, Lisa Cucolo, David S M Lee, Kristen E Pauken, Alexander C Huang, Tara C Gangadhar, Ravi K Amaravadi, Lynn M Schuchter, Michael D Feldman, Hemant Ishwaran, Robert H Vonderheide, Amit Maity, E John Wherry, Andy J Minn
Therapeutic blocking of the PD1 pathway results in significant tumor responses, but resistance is common. We demonstrate that prolonged interferon signaling orchestrates PDL1-dependent and PDL1-independent resistance to immune checkpoint blockade (ICB) and to combinations such as radiation plus anti-CTLA4. Persistent type II interferon signaling allows tumors to acquire STAT1-related epigenomic changes and augments expression of interferon-stimulated genes and ligands for multiple T cell inhibitory receptors...
December 1, 2016: Cell
https://www.readbyqxmd.com/read/27912060/the-hippo-pathway-kinases-lats1-2-suppress-cancer-immunity
#13
Toshiro Moroishi, Tomoko Hayashi, Wei-Wei Pan, Yu Fujita, Matthew V Holt, Jun Qin, Dennis A Carson, Kun-Liang Guan
Poorly immunogenic tumor cells evade host immunity and grow even in the presence of an intact immune system, but the complex mechanisms regulating tumor immunogenicity have not been elucidated. Here, we discovered an unexpected role of the Hippo pathway in suppressing anti-tumor immunity. We demonstrate that, in three different murine syngeneic tumor models (B16, SCC7, and 4T1), loss of the Hippo pathway kinases LATS1/2 (large tumor suppressor 1 and 2) in tumor cells inhibits tumor growth. Tumor regression by LATS1/2 deletion requires adaptive immune responses, and LATS1/2 deficiency enhances tumor vaccine efficacy...
December 1, 2016: Cell
https://www.readbyqxmd.com/read/27912059/microbiota-diurnal-rhythmicity-programs-host-transcriptome-oscillations
#14
Christoph A Thaiss, Maayan Levy, Tal Korem, Lenka Dohnalová, Hagit Shapiro, Diego A Jaitin, Eyal David, Deborah R Winter, Meital Gury-BenAri, Evgeny Tatirovsky, Timur Tuganbaev, Sara Federici, Niv Zmora, David Zeevi, Mally Dori-Bachash, Meirav Pevsner-Fischer, Elena Kartvelishvily, Alexander Brandis, Alon Harmelin, Oren Shibolet, Zamir Halpern, Kenya Honda, Ido Amit, Eran Segal, Eran Elinav
The intestinal microbiota undergoes diurnal compositional and functional oscillations that affect metabolic homeostasis, but the mechanisms by which the rhythmic microbiota influences host circadian activity remain elusive. Using integrated multi-omics and imaging approaches, we demonstrate that the gut microbiota features oscillating biogeographical localization and metabolome patterns that determine the rhythmic exposure of the intestinal epithelium to different bacterial species and their metabolites over the course of a day...
December 1, 2016: Cell
https://www.readbyqxmd.com/read/27912058/impaired-amino-acid-transport-at-the-blood-brain-barrier-is-a-cause-of-autism-spectrum-disorder
#15
Dora C Tărlungeanu, Elena Deliu, Christoph P Dotter, Majdi Kara, Philipp Christoph Janiesch, Mariafrancesca Scalise, Michele Galluccio, Mateja Tesulov, Emanuela Morelli, Fatma Mujgan Sonmez, Kaya Bilguvar, Ryuichi Ohgaki, Yoshikatsu Kanai, Anide Johansen, Seham Esharif, Tawfeg Ben-Omran, Meral Topcu, Avner Schlessinger, Cesare Indiveri, Kent E Duncan, Ahmet Okay Caglayan, Murat Gunel, Joseph G Gleeson, Gaia Novarino
Autism spectrum disorders (ASD) are a group of genetic disorders often overlapping with other neurological conditions. We previously described abnormalities in the branched-chain amino acid (BCAA) catabolic pathway as a cause of ASD. Here, we show that the solute carrier transporter 7a5 (SLC7A5), a large neutral amino acid transporter localized at the blood brain barrier (BBB), has an essential role in maintaining normal levels of brain BCAAs. In mice, deletion of Slc7a5 from the endothelial cells of the BBB leads to atypical brain amino acid profile, abnormal mRNA translation, and severe neurological abnormalities...
December 1, 2016: Cell
https://www.readbyqxmd.com/read/27912057/gut-microbiota-regulate-motor-deficits-and-neuroinflammation-in-a-model-of-parkinson-s-disease
#16
Timothy R Sampson, Justine W Debelius, Taren Thron, Stefan Janssen, Gauri G Shastri, Zehra Esra Ilhan, Collin Challis, Catherine E Schretter, Sandra Rocha, Viviana Gradinaru, Marie-Francoise Chesselet, Ali Keshavarzian, Kathleen M Shannon, Rosa Krajmalnik-Brown, Pernilla Wittung-Stafshede, Rob Knight, Sarkis K Mazmanian
The intestinal microbiota influence neurodevelopment, modulate behavior, and contribute to neurological disorders. However, a functional link between gut bacteria and neurodegenerative diseases remains unexplored. Synucleinopathies are characterized by aggregation of the protein α-synuclein (αSyn), often resulting in motor dysfunction as exemplified by Parkinson's disease (PD). Using mice that overexpress αSyn, we report herein that gut microbiota are required for motor deficits, microglia activation, and αSyn pathology...
December 1, 2016: Cell
https://www.readbyqxmd.com/read/27912056/conflict-resolution-in-the-genome-how-transcription-and-replication-make-it-work
#17
REVIEW
Stephan Hamperl, Karlene A Cimprich
The complex machineries involved in replication and transcription translocate along the same DNA template, often in opposing directions and at different rates. These processes routinely interfere with each other in prokaryotes, and mounting evidence now suggests that RNA polymerase complexes also encounter replication forks in higher eukaryotes. Indeed, cells rely on numerous mechanisms to avoid, tolerate, and resolve such transcription-replication conflicts, and the absence of these mechanisms can lead to catastrophic effects on genome stability and cell viability...
December 1, 2016: Cell
https://www.readbyqxmd.com/read/27912055/retromer-sets-a-trap-for-endosomal-cargo-sorting
#18
Ludger Johannes, Christian Wunder
Membrane trafficking from endosomes to the trans-Golgi network or the plasma membrane is driven by the retromer complex. Through structural analysis of the cargo-bound complex, Lucas et al. describe a mechanism by which endosomal membrane recruitment and cargo recognition are integrated through cooperative interactions between retromer subunits.
December 1, 2016: Cell
https://www.readbyqxmd.com/read/27912054/inner-secrets-of-the-respirasome
#19
Andrew Melber, Dennis R Winge
Structure determination by cryo-electron microscopy has approached atomic resolution and helped solve structures of large membrane-protein complexes that resisted crystallography. The 4.0 Å cryo-EM structure of one of the most intricate enzyme systems, the respirasome, in the mitochondrial inner membrane is reported in this issue of Cell.
December 1, 2016: Cell
https://www.readbyqxmd.com/read/27912053/formin-a-nuclear-protection
#20
Jörg Renkawitz, Michael Sixt
In this issue of Cell, Skau et al. show that the formin FMN2 organizes a perinuclear actin cytoskeleton that protects the nucleus and its genomic content of migrating cells squeezing through small spaces.
December 1, 2016: Cell
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