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Xiaomei Huang, Zixuan Cheng, Yanqi Huang, Cuishan Liang, Lan He, Zelan Ma, Xin Chen, Xiaomei Wu, Yexing Li, Changhong Liang, Zaiyi Liu
RATIONALE AND OBJECTIVES: To develop and validate a computed tomography-based radiomics signature for preoperatively discriminating high-grade from low-grade colorectal adenocarcinoma (CRAC). MATERIALS AND METHODS: This retrospective study was approved by our institutional review board, and the informed consent requirement was waived. This study enrolled 366 patients with CRAC (training dataset: n = 222, validation dataset: n = 144) from January 2008 to August 2015...
March 1, 2018: Academic Radiology
Brandon Sy, Julia Wong, Sander Granneman, David Tollervey, David Gally, Jai J Tree
Small regulatory nonprotein-coding RNAs (sRNAs) have emerged as ubiquitous and abundant regulators of gene expression in a diverse cross section of bacteria. They play key roles in most aspects of bacterial physiology, including central metabolism, nutrient acquisition, virulence, biofilm formation, and outer membrane composition. RNA sequencing technologies have accelerated the identification of bacterial regulatory RNAs and are now being employed to understand their functions. Many regulatory RNAs require protein partners for activity, or modulate the activity of interacting proteins...
2018: Methods in Molecular Biology
Marc Fahrner, Michael Stadlbauer, Martin Muik, Petr Rathner, Peter Stathopulos, Mitsu Ikura, Norbert Müller, Christoph Romanin
STIM1 and Orai1 are key components of the Ca2+ -release activated Ca2+ (CRAC) current. Orai1, which represents the subunit forming the CRAC channel complex, is activated by the ER resident Ca2+ sensor STIM1. The genetically inherited Stormorken syndrome disease has been associated with the STIM1 single point R304W mutant. The resulting constitutive activation of Orai1 mainly involves the CRAC-activating domain CAD/SOAR of STIM1, the exposure of which is regulated by the molecular interplay between three cytosolic STIM1 coiled-coil (CC) domains...
February 26, 2018: Nature Communications
Shuhua Zheng, Gilles M Leclerc, Bin Li, Ronan T Swords, Julio C Barredo
De novo and acquired drug resistance and subsequent relapse remain major challenges in acute lymphoblastic leukemia (ALL). We previously identified that pevonedistat (TAK-924, MLN4924), a first-in-class inhibitor of NEDD8 activating enzyme (NAE), elicits ER stress and has potent in vitro and in vivo efficacy against ALL. However, in pevonedistat-treated ALL cell lines, we found consistent activation of the pro-survival MEK/ERK pathway, which has been associated with relapse and poor outcome in ALL. We uncovered that inhibition of the MEK/ERK pathway in vitro and in vivo sensitized ALL cells to pevonedistat...
January 19, 2018: Oncotarget
Maya Miyoshi, Shuang Liu, Asuka Morizane, Erika Takemasa, Yashuyuki Suzuki, Takeshi Kiyoi, Kazutaka Maeyama, Masaki Mogi
The aim of this study was to investigate the efficacy and safety of YM-58483, a small molecular antagonist of Ca2+ release-activated Ca2+ (CRAC) channels, for the treatment of rheumatoid arthritis (RA), in vivo and ex vivo. YM-58483 was continuously injected subcutaneously in a collagen-induced arthritis (CIA) mouS.E.M.odel using an implanted osmotic pump. The severity of CIA was evaluated using the following parameters: body weight, hind paw volume, clinical score, histological analysis, cytokine levels, Ca2+ influx, and specific IgG production...
February 8, 2018: European Journal of Pharmacology
Xin Yang, Guorong Wen, Biguang Tuo, Fenglian Zhang, Hanxing Wan, Jialin He, Shiming Yang, Hui Dong
Background and Purpose: Although Ca2+ signaling may stimulate small intestinal ion secretion, little is known about its critical role and the molecular mechanisms of Ca2+-mediated biological action. Key Results: Activation of muscarinic receptors by carbachol(CCh) stimulated mouse duodenal Isc, which was significantly inhibited in Ca2+-free serosal solution and by several selective store-operated Ca2+ channels(SOC) blockers added to the serosal side of duodenal tissues...
January 9, 2018: Oncotarget
Petr Rathner, Michael Stadlbauer, Christoph Romanin, Marc Fahrner, Isabella Derler, Norbert Müller
We report a new NMR-scale purification procedure for two recombinant wild type fragments of the stromal interaction molecule 1 (STIM1). This protein acts as a calcium sensor in the endoplasmic reticulum (ER) and extends into the cytosol accumulating at ER - plasma membrane (PM) junctions upon calcium store depletion ultimately leading to activation of the Orai/CRAC channel. The functionally relevant cytosolic part of STIM1 consists of three coiled coil domains, which are mainly involved in intra- and inter-molecular homomeric interactions as well as coupling to and gating of CRAC channels...
February 1, 2018: Protein Expression and Purification
Jill L Thompson, Yue Zhao, Peter B Stathopulos, Alan Grossfield, Trevor J Shuttleworth
The low-conductance, highly calciumselective channels formed by the Orai proteins are known to take two major forms, namely the storeoperated CRAC channels, and store-independent, arachidonic acid-activated ARC channels. Both are activated by STIM1, but whereas CRAC channels are activated by the stromal-interacting STIM1 located in the endoplasmic reticulum membrane, ARC channels are activated by the minor pool of STIM1 located in the plasma membrane. Critically, maximally activated CRAC channel currents and ARC channel currents are completely additive within the same cell, demonstrating that these two channels are entirely distinct entities...
January 11, 2018: Journal of Biological Chemistry
Isabella Derler, Carmen Butorac, Adela Krizova, Michael Stadlbauer, Martin Muik, Marc Fahrner, Irene Frischauf, Christoph Romanin
Calcium (Ca2+) is an essential second messenger required for diverse signaling processes in immune cells. Ca2+ release-activated Ca2+ (CRAC) channels represent one main Ca2+ entry pathway into the cell. They are fully reconstituted via two proteins, the stromal interaction molecule 1 (STIM1), a Ca2+ sensor in the endoplasmic reticulum and the Ca2+ ion channel Orai in the plasma membrane. After Ca2+ store depletion, STIM1 and Orai couple to each other allowing Ca2+ influx. CRAC-/STIM1-mediated Orai channel currents display characteristic hallmarks such as high Ca2+ selectivity, an increase in current density when switching from a Ca2+-containing solution to a divalent-free Na+ one and fast Ca2+ dependent inactivation...
December 13, 2017: Journal of Biological Chemistry
Marc Fahrner, Saurabh K Pandey, Martin Muik, Lukas Traxler, Carmen Butorac, Michael Stadlbauer, Vasilina Zayats, Adéla Krizova, Peter Plenk, Irene Frischauf, Rainer Schindl, Hermann J Gruber, Peter Hinterdorfer, Rüdiger Ettrich, Christoph Romanin, Isabella Derler
Ca2+ release-activated Ca2+ (CRAC) channels constitute the major Ca2+ entry pathway into the cell. They are fully reconstituted via intermembrane coupling of the Ca2+ selective Orai channel and the Ca2+ sensing protein STIM1. In addition to the Orai C-terminus, the main coupling site for STIM1, the Orai N-terminus is indispensable for Orai channel gating. Although the extended transmembrane Orai N-terminal (ETON) region (Orai1: aa73-91; Orai3: aa48-65) is fully conserved in the Orai1 and Orai3 isoforms, Orai3 tolerates larger N-terminal truncations than Orai1 in retaining store-operated activation...
December 13, 2017: Journal of Biological Chemistry
Min-Kyung Yeo, Jin-Man Kim, Kwang-Sun Suh, Seok-Hyung Kim, Ok-Jun Lee, Kyung-Hee Kim
Partitioning defective (Par) proteins regulate cell polarity and differentiation. Par3, Par6β, and protein kinase Cζ (PKCζ), which are PAR complex members, have been shown to be associated with oncogenesis and progression. Herein, we report the expression pattern and clinical relevance of Par3, Par6β, and PKCζ in colorectal adenocarcinoma (CRAC). A total of 393 primary CRACs, 41 primary-metastatic CRAC pairs, 41 adenomas with low-grade dysplasia, and 41 nontumor colorectal tissue samples were examined by immunohistochemistry and Western blot assays for Par3, Par6β, and PKCζ protein expressions...
February 2018: Translational Oncology
James W Putney
Calcium signals arise by multiple mechanisms, including mechanisms of release of intracellular stored Ca2+ , and the influx of Ca2+ through channels in the plasma membrane. One mechanism that links these two sources of Ca2+ is store-operated Ca2+ entry, the most commonly encountered version of which involves the extensively studied calcium-release-activated Ca2+ (CRAC) channel. The minimal and essential molecular components of the CRAC channel are the STIM proteins that function as Ca2+ sensors in the endoplasmic reticulum, and the Orai proteins that comprise the pore forming subunits of the CRAC channel...
November 22, 2017: Advances in Biological Regulation
Shaqiu Zhang, Tamer Al-Maghout, Rosi Bissinger, Ni Zeng, Lisann Pelzl, Madhuri S Salker, Anchun Cheng, Yogesh Singh, Florian Lang
CD4+ T cells are key elements in immune responses and inflammation. Activation of T cell receptors in CD4+ T cells triggers cytosolic Ca2+ release with subsequent store operated Ca2+ entry (SOCE), which is accomplished by the pore forming Ca2+ release activated Ca2+ (CRAC) channel Orai1 and its regulator stromal cell-interaction molecule 2 (STIM2). Green tea polyphenol epigallocatechin-3-gallate (EGCG) acts as a potent anti-inflammatory and anti-oxidant agent for various types of cells including immune cells...
October 27, 2017: Oncotarget
Min-Kyung Yeo, Ji Yeon Kim, In-Ock Seong, Jin-Man Kim, Kyung-Hee Kim
Background: Protein kinase C zeta/lambda (PKCζ/λ) is a family of protein kinase enzymes that contributes to cell proliferation and regulation, which are important for cancer development. PKCζ/λ has been shown to be an important regulator of tumorigenesis in intestinal cancer. The phosphorylated form of PKCζ/λ, p-PKCζ/λ, is suggested as an active form of PKCζ/λ. However, p-PKCζ/λ expression and its clinicopathologic implication in colorectal adenocarcinoma (CRAC) are unclear. Methods: Seven whole-tissue sections of malignant polyps containing both non-neoplastic and neoplastic mucosa, 11 adenomas with low-grade dysplasia, and 173 CRACs were examined by immunohistochemistry and western blot assay for p-PKCζ/λ protein expression...
2017: Journal of Cancer
Jayson Lian, Mario Cuk, Sascha Kahlfuss, Lina Kozhaya, Martin Vaeth, Frédéric Rieux-Laucat, Capucine Picard, Melina J Benson, Antonia Jakovcevic, Karmen Bilic, Iva Martinac, Peter Stathopulos, Imre Kacskovics, Thomas Vraetz, Carsten Speckmann, Stephan Ehl, Thomas Issekutz, Derya Unutmaz, Stefan Feske
BACKGROUND: Store-operated Ca(2+) entry (SOCE) through Ca(2+) release-activated Ca(2+) (CRAC) channels is an essential signaling pathway in many cell types. CRAC channels are formed by ORAI1, ORAI2 and ORAI3 proteins and activated by stromal interaction molecule 1 (STIM1) and STIM2. Mutations in ORAI1 and STIM1 genes that abolish SOCE cause a combined immunodeficiency (CID) syndrome that is accompanied by autoimmunity and non-immunological symptoms. OBJECTIVE: Molecular and immunological analysis of patients with CID, anhidrosis and ectodermal dysplasia of unknown etiology...
November 15, 2017: Journal of Allergy and Clinical Immunology
Song Tan, Peng Zhang, Wei Xiao, Bing Feng, Lan-You Chen, Shuang Li, Peng Li, Wei-Zhong Zhao, Xiao-Ting Qi, Li-Ping Yin
Iron is essential for most living organisms. The iron-regulated transporter1 (IRT1) plays a major role in iron uptake in roots, and its trafficking from endoplasmic reticulum (ER) to plasma membrane (PM) is tightly coordinated with changes in iron environment. However, studies on the IRT1 response are limited. Here, we report that Malus xiaojinesis IRT1 (MxIRT1) associates with detergent-resistant membranes (DRMs, a biochemical counterpart of PM microdomains), whereas the PM microdomains are known platforms for signal transduction in the PM...
February 2018: Traffic
Pierre Luciano, Jongcheol Jeon, Abdessamad El-Kaoutari, Drice Challal, Amandine Bonnet, Mara Barucco, Tito Candelli, Frederic Jourquin, Pascale Lesage, Jaehoon Kim, Domenico Libri, Vincent Géli
The Set1 family of histone H3 lysine 4 (H3K4) methyltransferases is highly conserved from yeast to human. Here we show that the Set1 complex (Set1C) directly binds RNA in vitro through the regions that comprise the double RNA recognition motifs (dRRM) and N-SET domain within Set1 and its subunit Spp1. To investigate the functional relevance of RNA binding, we performed UV RNA crosslinking (CRAC) for Set1 and RNA polymerase II in parallel with ChIP-seq experiments. Set1 binds nascent transcripts through its dRRM...
2017: Cell Discovery
Ahmed S Warda, Jens Kretschmer, Philipp Hackert, Christof Lenz, Henning Urlaub, Claudia Höbartner, Katherine E Sloan, Markus T Bohnsack
N(6)-methyladenosine (m(6)A) is a highly dynamic RNA modification that has recently emerged as a key regulator of gene expression. While many m(6)A modifications are installed by the METTL3-METTL14 complex, others appear to be introduced independently, implying that additional human m(6)A methyltransferases remain to be identified. Using crosslinking and analysis of cDNA (CRAC), we reveal that the putative human m(6)A "writer" protein METTL16 binds to the U6 snRNA and other ncRNAs as well as numerous lncRNAs and pre-mRNAs...
November 2017: EMBO Reports
Martin Vaeth, Mate Maus, Stefan Klein-Hessling, Elizaveta Freinkman, Jun Yang, Miriam Eckstein, Scott Cameron, Stuart E Turvey, Edgar Serfling, Friederike Berberich-Siebelt, Richard Possemato, Stefan Feske
Store-operated Ca(2+) entry (SOCE) is the main Ca(2+) influx pathway in lymphocytes and is essential for T cell function and adaptive immunity. SOCE is mediated by Ca(2+) release-activated Ca(2+) (CRAC) channels that are activated by stromal interaction molecule (STIM) 1 and STIM2. SOCE regulates many Ca(2+)-dependent signaling molecules, including calcineurin, and inhibition of SOCE or calcineurin impairs antigen-dependent T cell proliferation. We here report that SOCE and calcineurin regulate cell cycle entry of quiescent T cells by controlling glycolysis and oxidative phosphorylation...
October 17, 2017: Immunity
John G Starkus, Peter Poerzgen, Kristine Layugan, Kelly Galbraith Kawabata, Jun-Ichi Goto, Sayuri Suzuki, George Myers, Michelle Kelly, Reinhold Penner, Andrea Fleig, F David Horgen
TRPM2 is a Ca2+ -permeable, nonselective cation channel that plays a role in oxidant-induced cell death, insulin secretion, and cytokine release. Few TRPM2 inhibitors have been reported, which hampers the validation of TRPM2 as a drug target. While screening our in-house marine-derived chemical library, we identified scalaradial and 12-deacetylscalaradial as the active components within an extract of an undescribed species of Cacospongia (class Demospongiae, family Thorectidae) that strongly inhibited TRPM2-mediated Ca2+ influx in TRPM2-overexpressing HEK293 cells...
October 27, 2017: Journal of Natural Products
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