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Craig S Pearson, Caitlin P Mencio, Amanda C Barber, Keith R Martin, Herbert M Geller
The failure of mammalian CNS neurons to regenerate their axons derives from a combination of intrinsic deficits and extrinsic factors. Following injury, chondroitin sulfate proteoglycans (CSPGs) within the glial scar inhibit axonal regeneration, an action mediated by the sulfated glycosaminoglycan (GAG) chains of CSPGs, especially those with 4-sulfated (4S) sugars. Arylsulfatase B (ARSB) selectively cleaves 4S groups from the non-reducing ends of GAG chains without disrupting other, growth-permissive motifs...
May 15, 2018: ELife
James Attwater, Aditya Raguram, Alexey S Morgunov, Edoardo Gianni, Philipp Holliger
RNA-catalyzed RNA replication is widely believed to have supported a primordial biology. However, RNA catalysis is dependent upon RNA folding, and this yields structures that can block replication of such RNAs. To address this apparent paradox we have re-examined the building blocks used for RNA replication. We report RNA-catalysed RNA synthesis on structured templates when using trinucleotide triphosphates (triplets) as substrates, catalysed by a general and accurate triplet polymerase ribozyme that emerged from in vitro evolution as a mutualistic RNA heterodimer...
May 15, 2018: ELife
Bryan J Matthews, David J Waxman
CTCF and cohesin are key drivers of 3D-nuclear organization, anchoring the megabase-scale Topologically Associating Domains (TADs) that segment the genome. Here, we present and validate a computational method to predict cohesin-and-CTCF binding sites that form intra-TAD DNA loops. The intra-TAD loop anchors identified are structurally indistinguishable from TAD anchors regarding binding partners, sequence conservation, and resistance to cohesin knockdown; further, the intra-TAD loops retain key functional features of TADs, including chromatin contact insulation, blockage of repressive histone mark spread, and ubiquity across tissues...
May 14, 2018: ELife
Thornton W Thompson, Benjamin T Jackson, P Jonathan Li, Jiaxi Wang, Alexander Byungsuk Kim, Kristen Ting Hui Huang, Lily Zhang, David H Raulet
NKG2D is an important immunoreceptor expressed on the surface of NK cells and some T cells. NKG2D recognizes a set of ligands typically expressed on infected or transformed cells, but recent studies have also documented NKG2D ligands on subsets of host non-tumor cells in tumor-bearing animals and humans. Here we show that in transplanted tumors and genetically engineered mouse cancer models, tumor-associated macrophages are induced to express the NKG2D ligand RAE-1δ. We find that a soluble factor produced by tumor cells is responsible for macrophage RAE-1δ induction, and we identify tumor-derived colony-stimulating factor-1 (CSF-1) as necessary and sufficient for macrophage RAE-1δ induction in vitro and in vivo ...
May 14, 2018: ELife
Povilas Karvelis, Aaron R Seitz, Stephen M Lawrie, Peggy Seriès
Recent theories propose that schizophrenia/schizotypy and autistic spectrum disorder are related to impairments in Bayesian inference i.e. how the brain integrates sensory information (likelihoods) with prior knowledge. However existing accounts fail to clarify: i) how proposed theories differ in accounts of ASD vs. schizophrenia and ii) whether the impairments result from weaker priors or enhanced likelihoods. Here, we directly address these issues by characterizing how 91 healthy participants, scored for autistic and schizotypal traits, implicitly learned and combined priors with sensory information...
May 14, 2018: ELife
Wenqi Yu, Dominique M Missiakas, Olaf Schneewind
Surface proteins of Staphylococcus aureus are secreted across septal membranes for assembly into the bacterial cross-wall. This localized secretion requires the YSIRK/GXXS motif signal peptide, however the mechanisms supporting precursor trafficking are not known. We show here that the signal peptide of staphylococcal protein A (SpA) is cleaved at the YSIRK/GXXS motif. A SpA signal peptide mutant defective for YSIRK/GXXS cleavage is also impaired for septal secretion and co-purifies with SecA, SecDF and LtaS...
May 14, 2018: ELife
Jun Qin, Kailun Wang, Lifan Sun, Haiying Xing, Sheng Wang, Lin Li, She Chen, Hui-Shan Guo, Jie Zhang
The vascular pathogen Verticillium dahliae infects the roots of plants to cause Verticillium wilt. The molecular mechanisms underlying V. dahliae virulence and host resistance remain elusive. Here, we demonstrate that a secretory protein, VdSCP41, functions as an intracellular effector that promotes V. dahliae virulence. The Arabidopsis master immune regulators CBP60g and SARD1 and cotton GhCBP60b are targeted by VdSCP41. VdSCP41 binds the C-terminal portion of CBP60g to inhibit its transcription factor activity...
May 14, 2018: ELife
Tin Ki Tsang, Eric A Bushong, Daniela Boassa, Junru Hu, Benedetto Romoli, Sebastien Phan, Davide Dulcis, Chih-Ying Su, Mark H Ellisman
Electron microscopy (EM) offers unparalleled power to study cell substructures at the nanoscale. Cryofixation by high-pressure freezing offers optimal morphological preservation, as it captures cellular structures instantaneously in their near-native states. However, the applicability of cryofixation is limited by its incompatibilities with diaminobenzidine labeling using genetic EM tags and the high-contrast en bloc staining required for serial block-face scanning electron microscopy (SBEM). In addition, it is challenging to perform correlated light and electron microscopy (CLEM) with cryofixed samples...
May 11, 2018: ELife
Rogier B Mars, Stamatios N Sotiropoulos, Richard E Passingham, Jerome Sallet, Lennart M Verhagen, Alexandre A Khrapitchev, Nicola Sibson, Saad Jbabdi
Comparing the brains of related species faces the challenges of establishing homologies whilst accommodating evolutionary specializations. Here we propose a general framework for understanding similarities and differences between the brains of primates. The approach uses white matter blueprints of the whole cortex based on a set of white matter tracts that can be anatomically matched across species. The blueprints provide a common reference space that allows us to navigate between brains of different species, identify homologous cortical areas, or to transform whole cortical maps from one species to the other...
May 11, 2018: ELife
Yue Wang, Yuan Shang, Jianchao Li, Weidi Chen, Gang Li, Jun Wan, Wei Liu, Mingjie Zhang
The Eph receptor tyrosine kinase (RTK) family is the largest subfamily of RTKs playing critical roles in many developmental processes such as tissue patterning, neurogenesis and neuronal circuit formation, angiogenesis, etc. How the 14 Eph proteins, via their highly similar cytoplasmic domains, can transmit diverse and sometimes opposite cellular signals upon engaging ephrins is a major unresolved question. Here we systematically investigated the bindings of each SAM domain of Eph receptors to the SAM domains from SHIP2 and Odin, and uncover a highly specific SAM-SAM interaction-mediated cytoplasmic Eph-effector binding pattern...
May 11, 2018: ELife
Kevin F Chau, Morgan L Shannon, Ryann M Fame, Erin Fonseca, Hillary Mullan, Matthew B Johnson, Anoop K Sendamarai, Mark W Springel, Benoit Laurent, Maria K Lehtinen
Forebrain precursor cells are dynamic during early brain development, yet the underlying molecular changes remain elusive. We observed major differences in transcriptional signatures of precursor cells from mouse forebrain at embryonic days E8.5 vs. E10.5 (before vs. after neural tube closure). Genes encoding protein biosynthetic machinery were strongly downregulated at E10.5. This was matched by decreases in ribosome biogenesis and protein synthesis, together with age-related changes in proteomic content of the adjacent fluids...
May 10, 2018: ELife
Zhou Yu, Lauren E Surface, Chong Yon Park, Max A Horlbeck, Gregory A Wyant, Monther Abu-Remaileh, Timothy R Peterson, David M Sabatini, Jonathan S Weissman, Erin K O'Shea
Nitrogen-containing-bisphosphonates (N-BPs) are a class of drugs widely prescribed to treat osteoporosis and other bone-related diseases. Although previous studies have established that N-BPs function by inhibiting the mevalonate pathway in osteoclasts, the mechanism by which N-BPs enter the cytosol from the extracellular space to reach their molecular target is not understood. Here we implemented a CRISPRi-mediated genome-wide screen and identified SLC37A3 (solute carrier family 37 member A3) as a gene required for the action of N-BPs in mammalian cells...
May 10, 2018: ELife
Takuya Akiyama, Sırma D User, Matthew C Gibson
The majority of mutations studied in animal models are designated as recessive based on the absence of visible phenotypes in germline heterozygotes. Accordingly, genetic studies primarily rely on homozygous loss-of-function to determine gene requirements, and a conceptually-related 'two-hit model' remains the central paradigm in cancer genetics. Here we investigate pathogenesis due to somatic mutation in epithelial tissues, a process that predominantly generates heterozygous cell clones. To study somatic mutation in Drosophila , we generated inducible alleles that mimic human Juvenile polyposis-associated BMPR1A mutations...
May 10, 2018: ELife
Zhe Zhang, Balázs Tóth, Andras Szollosi, Jue Chen, László Csanády
Transient Receptor Potential Melastatin 2 (TRPM2) is a Ca2+ -permeable cation channel required for immune cell activation, insulin secretion, and body heat control. TRPM2 is activated by cytosolic Ca2+ , phosphatidyl-inositol-4,5-bisphosphate and ADP ribose. Here we present the ~3Å resolution electron cryo-microscopy structure of TRPM2 from Nematostella vectensis , 63% similar in sequence to human TRPM2, in the Ca2+ -bound closed state. Compared to other TRPM channels, TRPM2 exhibits unique structural features that correlate with its function...
May 10, 2018: ELife
Ben Krause-Kyora, Julian Susat, Felix M Key, Denise Kühnert, Esther Bosse, Alexander Immel, Christoph Rinne, Sabin-Christin Kornell, Diego Yepes, Sören Franzenburg, Henrike O Heyne, Thomas Meier, Sandra Lösch, Harald Meller, Susanne Friederich, Nicole Nicklisch, Kurt W Alt, Stefan Schreiber, Andreas Tholey, Alexander Herbig, Almut Nebel, Johannes Krause
The hepatitis B virus (HBV) is one of the most widespread human pathogens known today, yet its origin and evolutionary history are still unclear and controversial. Here, we report the analysis of three ancient HBV genomes recovered from human skeletons found at three different archaeological sites in Germany. We reconstructed two Neolithic and one medieval HBV genomes by de novo assembly from shotgun DNA sequencing data. Additionally, we observed HBV-specific peptides using paleo-proteomics. Our results show that HBV circulates in the European population for at least 7000 years...
May 10, 2018: ELife
Jan J Zylicz, Maud Borensztein, Frederick Ck Wong, Yun Huang, Caroline Lee, Sabine Dietmann, M Azim Surani
Early mouse development is regulated and accompanied by dynamic changes in chromatin modifications, including G9a-mediated histone H3 lysine 9 dimethylation (H3K9me2). Previously, we provided insights into its role in post-implantation development (Zylicz et al., 2015). Here we explore the impact of depleting the maternally inherited G9a in oocytes on development shortly after fertilisation. We show that G9a accumulates typically at 4 to 8-cell stage to promote timely repression of a subset of 4-cell stage-specific genes...
May 10, 2018: ELife
Ewelina Betleja, Rashmi Nanjundappa, Tao Cheng, Moe R Mahjoub
The two centrioles of the centrosome in quiescent cells are inherently asymmetric structures that differ in age, morphology and function. How these asymmetric properties are established and maintained during quiescence remains unknown. Here we show that a daughter centriole-associated ciliopathy protein, Cep120, plays a critical inhibitory role at daughter centrioles. Depletion of Cep120 in quiescent mouse and human cells causes accumulation of pericentriolar material (PCM) components including Pericentrin, Cdk5Rap2, Ninein and Cep170...
May 9, 2018: ELife
Philipp Konrad Zuber, Irina Artsimovitch, Monali NandyMazumdar, Zhaokun Liu, Yuri Nedialkov, Kristian Schweimer, Paul Rösch, Stefan H Knauer
RfaH, a transcription regulator of the universally conserved NusG/Spt5 family, utilizes a unique mode of recruitment to elongating RNA polymerase to activate virulence genes. RfaH function depends critically on an ops sequence, an exemplar of a consensus pause, in the non-template DNA strand of the transcription bubble. We used structural and functional analyses to elucidate the role of ops in RfaH recruitment . Our results demonstrate that ops induces pausing to facilitate RfaH binding and establishes direct contacts with RfaH...
May 9, 2018: ELife
Madara Ratnadiwakara, Stuart K Archer, Craig I Dent, Igor Ruiz de Los Mozos, Traude H Beilharz, Anja S Knaupp, Christian M Nefzger, Jose M Polo, Minna-Liisa Anko
The establishment and maintenance of pluripotency depend on precise coordination of gene expression. We establish serine-arginine rich splicing factor 3 (SRSF3) as an essential regulator of RNAs encoding key components of the mouse pluripotency circuitry, SRSF3 ablation resulting in the loss of pluripotency and its overexpression enhancing reprogramming. Strikingly, SRSF3 binds to the core pluripotency transcription factor Nanog mRNA to facilitate its nucleo-cytoplasmic export independent of splicing. In the absence of SRSF3 binding, Nanog mRNA is sequestered in the nucleus and protein levels are severely downregulated...
May 9, 2018: ELife
Jie Geng, John D Altman, Sujatha Krishnakumar, Malini Raghavan
When complexed with antigenic peptides, human leukocyte antigen (HLA) class I (HLA-I) molecules initiate CD8+ T cell responses via interaction with the T cell receptor (TCR) and co-receptor CD8. Peptides are generally critical for the stable cell surface expression of HLA-I molecules. However, for HLA-I alleles such as HLA-B*35:01, peptide-deficient (empty) heterodimers are thermostable and detectable on the cell surface. Additionally, peptide-deficient HLA-B*35:01 tetramers preferentially bind CD8 and to a majority of blood-derived CD8+ T cells via a CD8-dependent binding mode...
May 9, 2018: ELife
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