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https://www.readbyqxmd.com/read/28767039/fxr1-regulates-transcription-and-is-required-for-tumor-growth-in-tp53-homozygous-deletion-human-cancers
#1
Yichao Fan, Jiao Yue, Mengtao Xiao, Han Han-Zhang, Yao Vickie Wang, Chun Ma, Zhilin Deng, Yingxiang Li, Yanyan Yu, Xinghao Wang, Shen Niu, Youjia Hua, Zhiping Weng, Peter Atadja, En Li, Bin Xiang
Tumor suppressor p53 prevents cell transformation by inducing apoptosis and other responses. Homozygous TP53 deletion occurs in various types of human cancers for which no therapeutic strategies have yet been reported. Based on TCGA database analysis, TP53 homozygous deletion locus mostly exhibits co-deletion of the neighboring gene FXR2, which belongs to the Fragile X gene family. Here, we demonstrate that inhibition of the remaining family member FXR1 selectively blocks cell proliferation in cancer cells containing homozygous deletion of both TP53 and FXR2 in a collateral lethality manner...
August 2, 2017: ELife
https://www.readbyqxmd.com/read/28767037/cryo-em-structure-of-the-saga-and-nua4-coactivator-subunit-tra1-at-3-7-angstrom-resolution
#2
Luis Miguel Diaz-Santin, Natasha Lukoyanova, Emir Aciyan, Alan Cm Cheung
Coactivator complexes SAGA and NuA4 stimulate transcription by post-translationally modifying chromatin. Both complexes contain the Tra1 subunit, a highly conserved 3744-residue protein from the Phosphoinositide 3-Kinase-related kinase (PIKK) family and a direct target for multiple sequence-specific activators. We present the Cryo-EM structure of Saccharomyces cerevsisae Tra1 to 3.7 Å resolution, revealing an extensive network of alpha-helical solenoids organized into a diamond ring conformation and is strikingly reminiscent of DNA-PKcs, suggesting a direct role for Tra1 in DNA repair...
August 2, 2017: ELife
https://www.readbyqxmd.com/read/28762945/structural-dynamics-of-rbma-governs-plasticity-of-vibrio-cholerae-biofilms
#3
Jiunn Cn Fong, Andrew Rogers, Alicia K Michael, Nicole C Parsley, William-Cole Cornell, Yu-Cheng Lin, Praveen K Singh, Raimo Hartmann, Knut Drescher, Evgeny Vinogradov, Lars Ep Dietrich, Carrie L Partch, Fitnat H Yildiz
Biofilm formation is critical for the infection cycle of Vibrio cholerae. Vibrio exopolysaccharides (VPS) and the matrix proteins RbmA, Bap1 and RbmC are required for the development of biofilm architecture. We demonstrate that RbmA binds VPS directly and uses a binary structural switch within its first fibronectin type III (FnIII-1) domain to control RbmA structural dynamics and the formation of VPS-dependent higher-order structures. The structural switch in FnIII-1 regulates interactions in trans with the FnIII-2 domain, leading to open (monomeric) or closed (dimeric) interfaces...
August 1, 2017: ELife
https://www.readbyqxmd.com/read/28762944/synaptic-plasticity-through-activation-of-glua3-containing-ampa-receptors
#4
Maria C Renner, Eva Hh Albers, Nicolas Gutierrez-Castellanos, Niels R Reinders, Aile N van Huijstee, Hui Xiong, Tessa R Lodder, Helmut W Kessels
Excitatory synaptic transmission is mediated by AMPA-type glutamate receptors (AMPARs). In CA1 pyramidal neurons of the hippocampus two types of AMPARs predominate: those that contain subunits GluA1 and GluA2 (GluA1/2), and those that contain GluA2 and GluA3 (GluA2/3). Whereas subunits GluA1 and GluA2 have been extensively studied, the contribution of GluA3 to synapse physiology has remained unclear. Here we show in mice that GluA2/3s are in a low-conductance state under basal conditions, and although present at synapses they contribute little to synaptic currents...
August 1, 2017: ELife
https://www.readbyqxmd.com/read/28758638/influenza-virus-recruits-host-protein-kinase-c-to-control-assembly-and-activity-of-its-replication-machinery
#5
Arindam Mondal, Anthony R Dawson, Gregory K Potts, Elyse C Freiberger, Steven F Baker, Lindsey A Moser, Kristen A Bernard, Joshua J Coon, Andrew Mehle
Influenza virus expresses transcripts early in infection and transitions towards genome replication at later time points. This process requires de novo assembly of the viral replication machinery, large ribonucleoprotein complexes (RNPs) composed of the viral polymerase, genomic RNA and oligomeric nucleoprotein (NP). Despite the central role of RNPs during infection, the factors dictating where and when they assemble are poorly understood. Here we demonstrate that human protein kinase C (PKC) family members regulate RNP assembly...
July 31, 2017: ELife
https://www.readbyqxmd.com/read/28753127/igf2-mrna-binding-protein-2-is-a-tumor-promoter-that-drives-cancer-proliferation-through-its-client-mrnas-igf2-and-hmga1
#6
Ning Dai, Fei Ji, Jason Wright, Liliana Minichiello, Ruslan I Sadreyev, Joseph Avruch
The gene encoding the Insulin-like Growth Factor 2 mRNA binding protein 2/IMP2 is amplified and overexpressed in many human cancers, accompanied by a poorer prognosis. Mice lacking IMP2 exhibit a longer lifespan and a reduced tumor burden at old age. Herein we show in a diverse array of human cancer cells that IMP2 overexpression stimulates and IMP2 elimination diminishes proliferation by 50-80%. In addition to its known ability to promote the abundance of Insulin-like Growth Factor 2/IGF2, we find that IMP2 strongly promotes IGF action, by binding and stabilizing the mRNA encoding the DNA binding protein HMGA1, a known oncogene...
July 28, 2017: ELife
https://www.readbyqxmd.com/read/28753126/structure-and-topology-around-the-cleavage-site-regulate-post-translational-cleavage-of-the-hiv-1-gp160-signal-peptide
#7
Erik Lee Snapp, Nicholas McCaul, Matthias Quandte, Zuzana Cabartova, Ilja Bontjer, Carolina Källgren, IngMarie Nilsson, Aafke Land, Gunnar von Heijne, Rogier W Sanders, Ineke Braakman
Like all other secretory proteins, the HIV-1 envelope glycoprotein gp160, is targeted to the endoplasmic reticulum (ER) by its signal peptide during synthesis. Proper gp160 folding in the ER requires core glycosylation, disulfide-bond formation and proline isomerization. Signal-peptide cleavage occurs only late after gp160 chain termination and is dependent on folding of the soluble subunit gp120 to a near-native conformation. We here detail the mechanism by which co-translational signal-peptide cleavage is prevented...
July 28, 2017: ELife
https://www.readbyqxmd.com/read/28753125/reaction-times-can-reflect-habits-rather-than-computations
#8
Aaron L Wong, Jeff Goldsmith, Alexander D Forrence, Adrian M Haith, John W Krakauer
Reaction times (RTs) are assumed to reflect the underlying computations required for making decisions and preparing actions. However, recent work has shown that movements can be initiated earlier than typically expressed without affecting performance; hence, the RT may be modulated by factors other than computation time. Consistent with that view, we demonstrated that RTs are influenced by prior experience: when a previously performed task required a specific RT to support task success, this biased the RTs in future tasks...
July 28, 2017: ELife
https://www.readbyqxmd.com/read/28749340/super-resolution-imaging-of-synaptic-and-extra-synaptic-ampa-receptors-with-different-sized-fluorescent-probes
#9
Sang Hak Lee, Chaoyi Jin, En Cai, Pinghua Ge, Yuji Ishitsuka, Kai Wen Teng, Andre A de Thomaz, Duncan L Nall, Murat Baday, Okunola Jeyifous, Daniel Demonte, Christopher M Dundas, Sheldon Park, Jary Y Delgado, William N Green, Paul R Selvin
Previous studies tracking AMPA receptor (AMPAR) diffusion at synapses observed a large mobile extrasynaptic AMPAR pool. Using super-resolution microscopy, we examined how fluorophore size and photostability affected AMPAR trafficking outside of, and within, post-synaptic densities (PSDs) from rats. Organic fluorescent dyes (≈4 nm), quantum dots, either small (≈10 nm diameter; sQDs) or big (>20 nm; bQDs), were coupled to AMPARs via different-sized linkers. We find that >90% of AMPARs labeled with fluorescent dyes or sQDs were diffusing in confined nanodomains in PSDs, which were stable for 15 minutes or longer...
July 27, 2017: ELife
https://www.readbyqxmd.com/read/28749339/pten-controls-glandular-morphogenesis-through-a-juxtamembrane-%C3%AE-arrestin1-arhgap21-scaffolding-complex
#10
Arman Javadi, Ravi K Deevi, Emma Evergren, Elodie Blondel-Tepaz, George S Baillie, Mark Gh Scott, Frederick Charles Campbell
PTEN controls three-dimensional (3D) glandular morphogenesis by coupling juxtamembrane signalling to mitotic spindle machinery. While molecular mechanisms remain unclear, PTEN interacts through its C2 membrane-binding domain with the scaffold protein β-Arrestin1. Because β-Arrestin1 binds and suppresses the Cdc42 GTPase-activating protein ARHGAP21, we hypothesize that PTEN controls Cdc42-dependent morphogenic processes through a β-Arrestin1-ARHGAP21 complex. Here we show that PTEN knockdown (KD) impairs β-Arrestin1 membrane localization, β-Arrestin1-ARHGAP21 interactions, Cdc42 activation, mitotic spindle orientation and 3D glandular morphogenesis...
July 27, 2017: ELife
https://www.readbyqxmd.com/read/28749338/fast-two-photon-imaging-of-subcellular-voltage-dynamics-in-neuronal-tissue-with-genetically-encoded-indicators
#11
Simon Chamberland, Helen H Yang, Michael M Pan, Stephen W Evans, Sihui Guan, Mariya Chavarha, Ying Yang, Charleen Salesse, Haodi Wu, Joseph C Wu, Thomas R Clandinin, Katalin Toth, Michael Z Lin, François St-Pierre
Monitoring voltage dynamics in defined neurons deep in the brain is critical for unraveling the function of neuronal circuits, but is challenging due to the limited performance of existing tools. In particular, while genetically encoded voltage indicators have shown promise for optical detection of voltage transients, many indicators exhibit low sensitivity when imaged under two-photon illumination. Previous studies thus fell short of visualizing voltage dynamics in individual neurons in single trials. Here, we report ASAP2s, a novel voltage indicator with improved sensitivity...
July 27, 2017: ELife
https://www.readbyqxmd.com/read/28745584/the-heritability-of-multi-modal-connectivity-in-human-brain-activity
#12
Giles L Colclough, Stephen M Smith, Tom E Nichols, Anderson M Winkler, Stamatios N Sotiropoulos, Matthew F Glasser, David C Van Essen, Mark W Woolrich
Patterns of intrinsic human brain activity exhibit a profile of functional connectivity that is associated with behaviour and cognitive performance, and deteriorates with disease. This paper investigates the relative importance of genetic factors and the common environment between twins in determining this functional connectivity profile. Using functional magnetic resonance imaging (fMRI) on 820 subjects from the Human Connectome Project, and magnetoencephalographic (MEG) recordings from a subset, the heritability of connectivity between 39 cortical regions was estimated...
July 26, 2017: ELife
https://www.readbyqxmd.com/read/28742026/aire-is-a-critical-spindle-associated-protein-in-embryonic-stem-cells
#13
Bin Gu, Jean-Philippe Lambert, Katie Cockburn, Anne-Claude Gingras, Janet Rossant
Embryonic stem (ES) cells go though embryo-like cell cycles regulated by specialized molecular mechanisms. However, it is not known whether there are ES cell-specific mechanisms regulating mitotic fidelity. Here we showed that Autoimmune Regulator (Aire), a transcription coordinator involved in immune tolerance processes, is a critical spindle-associated protein in mouse ES(mES) cells. BioID analysis showed that AIRE associates with spindle-associated proteins in mES cells. Loss of function analysis revealed that Aire was important for centrosome number regulation and spindle pole integrity specifically in mES cells...
July 25, 2017: ELife
https://www.readbyqxmd.com/read/28742025/structure-and-reconstitution-of-yeast-mpp6-nuclear-exosome-complexes-reveals-that-mpp6-stimulates-rna-decay-and-recruits-the-mtr4-helicase
#14
Elizabeth V Wasmuth, John C Zinder, Dimitrios Zattas, Mom Das, Christopher D Lima
Nuclear RNA exosomes catalyze a range of RNA processing and decay activities that are coordinated in part by cofactors, including Mpp6, Rrp47, and the Mtr4 RNA helicase. Mpp6 interacts with the nine-subunit exosome core, while Rrp47 stabilizes the exoribonuclease Rrp6 and recruits Mtr4, but it is less clear if these cofactors work together. Using biochemistry with Saccharomyces cerevisiae proteins, we show that Rrp47 and Mpp6 stimulate exosome-mediated RNA decay, albeit with unique dependencies on elements within the nuclear exosome...
July 25, 2017: ELife
https://www.readbyqxmd.com/read/28742023/genome-wide-identification-of-lineage-and-locus-specific-variation-associated-with-pneumococcal-carriage-duration
#15
John A Lees, Nicholas J Croucher, David Goldblatt, François Nosten, Julian Parkhill, Claudia Turner, Paul Turner, Stephen D Bentley
Streptococcus pneumoniae is a leading cause of invasive disease in infants, especially in low-income settings. Asymptomatic carriage in the nasopharynx is a prerequisite for disease, but variability in its duration is currently only understood at the serotype level. Here we developed a model to calculate the duration of carriage episodes from longitudinal swab data, and combined these results with whole genome sequence data. We estimated that pneumococcal genomic variation accounted for 63% of the phenotype variation, whereas the host traits considered here (age and previous carriage) accounted for less than 5%...
July 25, 2017: ELife
https://www.readbyqxmd.com/read/28742022/modeling-of-axonal-endoplasmic-reticulum-network-by-spastic-paraplegia-proteins
#16
Belgin Yalçın, Lu Zhao, Martin Stofanko, Niamh C O'Sullivan, Zi Han Kang, Annika Roost, Matthew R Thomas, Sophie Zaessinger, Olivier Blard, Alex L Patto, Anood Sohail, Valentina Baena, Mark Terasaki, Cahir J O'Kane
Axons contain a smooth tubular endoplasmic reticulum (ER) network that is thought to be continuous with ER throughout the neuron; the mechanisms that form this axonal network are unknown. Mutations affecting reticulon or REEP proteins, with intramembrane hairpin domains that model ER membranes, cause an axon degenerative disease, hereditary spastic paraplegia (HSP). We show that Drosophila axons have a dynamic axonal ER network, which these proteins help to model. Loss of HSP hairpin proteins causes ER sheet expansion, partial loss of ER from distal motor axons, and occasional discontinuities in axonal ER...
July 25, 2017: ELife
https://www.readbyqxmd.com/read/28742021/resolving-the-prevalence-of-somatic-transposition-in-drosophila
#17
Christoph Daniel Treiber, Scott Waddell
Somatic transposition in mammals and insects could increase cellular diversity and neural mobilization has been implicated in age-dependent decline. To understand the impact of transposition in somatic cells it is essential to reliably measure the frequency and map locations of new insertions. Here we identified thousands of putative somatic transposon insertions in neurons from individual Drosophila melanogaster using whole-genome sequencing. However, the number of de novo insertions did not correlate with transposon expression or fly age...
July 25, 2017: ELife
https://www.readbyqxmd.com/read/28737489/nfatc2-enhances-tumor-initiating-phenotypes-through-the-nfatc2-sox2-aldh-axis-in-lung-adenocarcinoma
#18
Zhi-Jie Xiao, Jing Liu, Si-Qi Wang, Yun Zhu, Xu-Yuan Gao, Vicky Pui-Chi Tin, Jing Qin, Jun-Wen Wang, Maria Pik Wong
Tumor initiating cells (TIC) are dynamic cancer cell subsets that display enhanced tumor functions and resilience to treatment but the mechanism of TIC induction or maintenance in lung cancer is not fully understood. In this study, we show the calcium pathway transcription factor NFATc2 is a novel regulator of lung TIC phenotypes, including tumorspheres, cell motility, tumorigenesis, as well as in vitro and in vivo responses to chemotherapy and targeted therapy. In human lung cancers, high NFATc2 expression predicted poor tumor differentiation, adverse recurrence-free and cancer-specific overall survivals...
July 24, 2017: ELife
https://www.readbyqxmd.com/read/28731408/defining-the-biological-basis-of-radiomic-phenotypes-in-lung-cancer
#19
Patrick Grossmann, Olya Stringfield, Nehme El-Hachem, Marilyn M Bui, Emmanuel Rios Velazquez, Chintan Parmar, Ralph Th Leijenaar, Benjamin Haibe-Kains, Philippe Lambin, Robert Gillies, Hugo Jwl Aerts
Medical imaging can visualize characteristics of human cancer noninvasively. Radiomics is an emerging field that translates these medical images into quantitative data to enable phenotypic profiling of tumors. While radiomics has been associated with several clinical endpoints, the complex relationships of radiomics, clinical factors, and tumor biology are largely unknown. To this end, we analyzed two independent cohorts of respectively 262 North American and 89 European patients with lung cancer, and consistently identified previously undescribed associations between radiomic imaging features, molecular pathways, and clinical factors...
July 21, 2017: ELife
https://www.readbyqxmd.com/read/28731407/t-cell-receptor-repertoires-of-mice-and-humans-are-clustered-in-similarity-networks-around-conserved-public-cdr3-sequences
#20
Asaf Madi, Asaf Poran, Eric Shifrut, Shlomit Reich-Zeliger, Erez Greenstein, Irena Zaretsky, Tomer Arnon, Francois Van Laethem, Alfred Singer, Jinghua Lu, Peter D Sun, Irun R Cohen, Nir Friedman
Diversity of T cell receptor (TCR) repertoires, generated by somatic DNA rearrangements, is central to immune system function. However, the level of sequence similarity of TCR repertoires within and between species has not been characterized. Using network analysis of high-throughput TCR sequencing data, we found that abundant CDR3-TCRβ sequences were clustered within networks generated by sequence similarity. We discovered a substantial number of public CDR3-TCRβ segments that were identical in mice and humans...
July 21, 2017: ELife
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