Table S4. Trophoblast Differentiation-Associated Genes
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Constitutive Phospholipid Scramblase Activity of a G Protein-Coupled Receptor
ARTICLE Received 19 Feb 2014 | Accepted 1 Sep 2014 | Published 8 Oct 2014 DOI: 10.1038/ncomms6115 Constitutive phospholipid scramblase activity of a G protein-coupled receptor Michael A. Goren1, Takefumi Morizumi2, Indu Menon1, Jeremiah S. Joseph3,w, Jeremy S. Dittman1, Vadim Cherezov3, Raymond C. Stevens3, Oliver P. Ernst2,4 & Anant K. Menon1 Opsin, the rhodopsin apoprotein, was recently shown to be an ATP-independent flippase (or scramblase) that equilibrates phospholipids across photoreceptor disc membranes in mammalian retina, a process required for disc homoeostasis. Here we show that scrambling is a constitutive activity of rhodopsin, distinct from its light-sensing function. Upon reconstitution into vesicles, discrete conformational states of the protein (rhodopsin, a metarhodopsin II-mimic, and two forms of opsin) facilitated rapid (410,000 phospholipids per protein per second) scrambling of phospholipid probes. Our results indicate that the large conformational changes involved in converting rhodopsin to metarhodopsin II are not required for scrambling, and that the lipid translocation pathway either lies near the protein surface or involves membrane packing defects in the vicinity of the protein. In addition, we demonstrate that b2-adrenergic and adenosine A2A receptors scramble lipids, suggesting that rhodopsin-like G protein-coupled receptors may play an unexpected moonlighting role in re-modelling cell membranes. 1 Department of Biochemistry, Weill Cornell Medical College, New York, New York 10065, USA. 2 Department of Biochemistry, University of Toronto, Toronto, Ontario, Canada M5S 1A8. 3 Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, California 92037, USA. 4 Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada M5S 1A8. -
The Title of the Article
Mechanism-Anchored Profiling Derived from Epigenetic Networks Predicts Outcome in Acute Lymphoblastic Leukemia Xinan Yang, PhD1, Yong Huang, MD1, James L Chen, MD1, Jianming Xie, MSc2, Xiao Sun, PhD2, Yves A Lussier, MD1,3,4§ 1Center for Biomedical Informatics and Section of Genetic Medicine, Department of Medicine, The University of Chicago, Chicago, IL 60637 USA 2State Key Laboratory of Bioelectronics, Southeast University, 210096 Nanjing, P.R.China 3The University of Chicago Cancer Research Center, and The Ludwig Center for Metastasis Research, The University of Chicago, Chicago, IL 60637 USA 4The Institute for Genomics and Systems Biology, and the Computational Institute, The University of Chicago, Chicago, IL 60637 USA §Corresponding author Email addresses: XY: [email protected] YH: [email protected] JC: [email protected] JX: [email protected] XS: [email protected] YL: [email protected] - 1 - Abstract Background Current outcome predictors based on “molecular profiling” rely on gene lists selected without consideration for their molecular mechanisms. This study was designed to demonstrate that we could learn about genes related to a specific mechanism and further use this knowledge to predict outcome in patients – a paradigm shift towards accurate “mechanism-anchored profiling”. We propose a novel algorithm, PGnet, which predicts a tripartite mechanism-anchored network associated to epigenetic regulation consisting of phenotypes, genes and mechanisms. Genes termed as GEMs in this network meet all of the following criteria: (i) they are co-expressed with genes known to be involved in the biological mechanism of interest, (ii) they are also differentially expressed between distinct phenotypes relevant to the study, and (iii) as a biomodule, genes correlate with both the mechanism and the phenotype. -
Phospholipid Ebb and Flow Makes Mitochondria Go
REVIEW Phospholipid ebb and flow makes mitochondria go Michelle Grace Acoba, Nanami Senoo, and Steven M. Claypool Mitochondria, so much more than just being energy factories, also have the capacity to synthesize macromolecules including phospholipids, particularly cardiolipin (CL) and phosphatidylethanolamine (PE). Phospholipids are vital constituents of mitochondrial membranes, impacting the plethora of functions performed by this organelle. Hence, the orchestrated movement of phospholipids to and from the mitochondrion is essential for cellular integrity. In this review, we capture recent advances in the field of mitochondrial phospholipid biosynthesis and trafficking, highlighting the significance of interorganellar communication, intramitochondrial contact sites, and lipid transfer proteins in maintaining membrane homeostasis. We then discuss the physiological functions of CL and PE, specifically how they associate with protein complexes in mitochondrial membranes to support bioenergetics and maintain mitochondrial architecture. Introduction (PS), phosphatidylinositol (PI), and phosphatidylcholine (PC), as Biological membranes give a means of regulated communi- well as sphingolipids, cholesterol, and many lysophospholipids, it cation, as the lipid bilayer itself acts as a platform for many has to recruit from other organelles. This section will focus on the reactions. The amphipathic nature of lipids underlies the mitochondrion’s contribution to the generation of two highly creation of a bilayer; the hydrophobic acyl chains cluster at abundant phospholipids in its membranes: CL and PE (Fig. 1). the middle to get buried, while the hydrophilic head groups face the aqueous surroundings. A diverse array of lipids, in- CL metabolism cluding glycerophospholipids, sphingolipids, and sterols, present CL production. CL is the defining membrane constituent of in different amounts, gives a biological membrane its identity the mitochondrion, the organelle in which it is made (Fig. -
Table 2. Significant
Table 2. Significant (Q < 0.05 and |d | > 0.5) transcripts from the meta-analysis Gene Chr Mb Gene Name Affy ProbeSet cDNA_IDs d HAP/LAP d HAP/LAP d d IS Average d Ztest P values Q-value Symbol ID (study #5) 1 2 STS B2m 2 122 beta-2 microglobulin 1452428_a_at AI848245 1.75334941 4 3.2 4 3.2316485 1.07398E-09 5.69E-08 Man2b1 8 84.4 mannosidase 2, alpha B1 1416340_a_at H4049B01 3.75722111 3.87309653 2.1 1.6 2.84852656 5.32443E-07 1.58E-05 1110032A03Rik 9 50.9 RIKEN cDNA 1110032A03 gene 1417211_a_at H4035E05 4 1.66015788 4 1.7 2.82772795 2.94266E-05 0.000527 NA 9 48.5 --- 1456111_at 3.43701477 1.85785922 4 2 2.8237185 9.97969E-08 3.48E-06 Scn4b 9 45.3 Sodium channel, type IV, beta 1434008_at AI844796 3.79536664 1.63774235 3.3 2.3 2.75319499 1.48057E-08 6.21E-07 polypeptide Gadd45gip1 8 84.1 RIKEN cDNA 2310040G17 gene 1417619_at 4 3.38875643 1.4 2 2.69163229 8.84279E-06 0.0001904 BC056474 15 12.1 Mus musculus cDNA clone 1424117_at H3030A06 3.95752801 2.42838452 1.9 2.2 2.62132809 1.3344E-08 5.66E-07 MGC:67360 IMAGE:6823629, complete cds NA 4 153 guanine nucleotide binding protein, 1454696_at -3.46081884 -4 -1.3 -1.6 -2.6026947 8.58458E-05 0.0012617 beta 1 Gnb1 4 153 guanine nucleotide binding protein, 1417432_a_at H3094D02 -3.13334396 -4 -1.6 -1.7 -2.5946297 1.04542E-05 0.0002202 beta 1 Gadd45gip1 8 84.1 RAD23a homolog (S. -
Phosphatidylserine in Non-Apoptotic Cell Death Inbar Shlomovitz1, Mary Speir2,3 and Motti Gerlic1*
Shlomovitz et al. Cell Communication and Signaling (2019) 17:139 https://doi.org/10.1186/s12964-019-0437-0 REVIEW Open Access Flipping the dogma – phosphatidylserine in non-apoptotic cell death Inbar Shlomovitz1, Mary Speir2,3 and Motti Gerlic1* Abstract The exposure of phosphatidylserine (PS) on the outer plasma membrane has long been considered a unique feature of apoptotic cells. Together with other “eat me” signals, it enables the recognition and phagocytosis of dying cells (efferocytosis), helping to explain the immunologically-silent nature of apoptosis. Recently, however, PS exposure has also been reported in non-apoptotic forms of regulated inflammatory cell death, such as necroptosis, challenging previous dogma. In this review, we outline the evidence for PS exposure in non-apoptotic cells and extracellular vesicles (EVs), and discuss possible mechanisms based on our knowledge of apoptotic-PS exposure. In addition, we examine the outcomes of non-apoptotic PS exposure, including the reversibility of cell death, efferocytosis, and consequent inflammation. By examining PS biology, we challenge the established approach of distinguishing apoptosis from other cell death pathways by AnnexinV staining of PS externalization. Finally, we re- evaluate how PS exposure is thought to define apoptosis as an immunologically silent process distinct from other non-apoptotic and inflammatory cell death pathways. Ultimately, we suggest that a complete understanding of how regulated cell death processes affect the immune system is far from being fully -
Atnea1-Identification and Characterization of a Novel Plant Nuclear Envelope Associated Protein
Vol. 13(7), pp. 844-856, 12 February, 2014 DOI: 10.5897/AJB2013.13078 ISSN 1684-5315 ©2014 Academic Journals African Journal of Biotechnology http://www.academicjournals.org/AJB Full Length Research Paper AtNEA1-identification and characterization of a novel plant nuclear envelope associated protein Ting Lu Department of Biological and Medical Sciences, Oxford Brookes University, Oxford OX3 0BP, UK. Accepted 29 January, 2014 In animal and yeast cells, a cross nuclear envelope structure linker of nucleoskeleton and cytoskeleton (LINC) is formed by outer nuclear membrane SUN proteins and inner nuclear membrane KASH proteins. However, little information was acquired about plant SUN-KASH structure until they were found in plant SUN proteins in 2010 and KASH proteins in 2012. The SUN-KASH complex alongside with actin in the microfilament cytoskeleton and nucleaoskeleton together shape the main cell skeleton structure and involve in many important biological functions including cell structure stability, cell movement and cell division. In searching of other plant nuclear envelope associated proteins, arabidopsis nuclear envelop associated (AtNEA1) protein 1, a plant nucleoplasmic protein, was identified from biological studies. AtNEA1 was predicted to have a nuclear localisation signal (NLS), two coiled coil domains and one transmembrane (TM) domain. The mutants with the deletion of respective putative domains were observed under confocal microscopy. The subcellular localisation of mutants implied that putative NLS is not essential for AtNEA1 to diffuse through NPC but can strongly increase the efficiency, both coiled coil domains participate in the interaction of AtNEA1 with its unknown INM intrinsic interaction partner, and putative TM appeared to be non-functional. -
Identification of Plant SUN Domain-Interacting Tail Proteins and Analysis of Their Function in Nuclear Positioning
Identification of Plant SUN Domain-Interacting Tail Proteins and Analysis of Their Function in Nuclear Positioning DISSERTATION Presented in Partial Fulfillment of the Requirements for the Degree Doctor of Philosophy in the Graduate School of the Ohio State University By Xiao Zhou, M. S. Graduate Program in Plant Cellular and Molecular Biology The Ohio State University 2013 Dissertation Committee: Professor Iris Meier, Advisor Professor Biao Ding Professor Stephen Osmani Professor R. Keith Slotkin Copyright by Xiao Zhou 2013 Abstract The nuclear envelope (NE) is a double membrane system consisting of an inner nuclear membrane (INM) and an outer nuclear membrane (ONM). Studies in opisthokonts revealed that the two membranes are bridged by protein complexes formed by the INM Sad1/UNC-84 (SUN) proteins and the ONM Klarsicht/ANC-1/Syne-1 homology (KASH) proteins. These SUN-KASH NE bridges are usually linkers of the nucleoskeleton to the cytoskeleton (LINC) conserved across eukaryotes. LINC complexes are key players in multiple cellular processes, such as nuclear and chromosomal positioning and nuclear shape determination, which in turn influence the gametogenesis and several aspects of development. Although these cellular processes have long been also known in plants, no KASH proteins are encoded in the plant genomes. I identified WPP domain interacting proteins (WIPs) as the first plant KASH protein analogs. WIPs are plant-specific ONM proteins that redundantly anchor Ran GTPase activating protein (RanGAP) to the NE. Arabidopsis thaliana WIPs (AtWIPs) interact with Arabidopsis thaliana SUN proteins (AtSUNs), which is required for both AtWIP1 and AtRanGAP1 NE localization. In addition, AtWIPs and AtSUNs are necessary for maintaining the elongated nuclear shape of Arabidopsis epidermal cells. -
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PROBING THE INTERACTION OF ASPERGILLUS FUMIGATUS CONIDIA AND HUMAN AIRWAY EPITHELIAL CELLS BY TRANSCRIPTIONAL PROFILING IN BOTH SPECIES by POL GOMEZ B.Sc., The University of British Columbia, 2002 A THESIS SUBMITTED IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF MASTER OF SCIENCE in THE FACULTY OF GRADUATE STUDIES (Experimental Medicine) THE UNIVERSITY OF BRITISH COLUMBIA (Vancouver) January 2010 © Pol Gomez, 2010 ABSTRACT The cells of the airway epithelium play critical roles in host defense to inhaled irritants, and in asthma pathogenesis. These cells are constantly exposed to environmental factors, including the conidia of the ubiquitous mould Aspergillus fumigatus, which are small enough to reach the alveoli. A. fumigatus is associated with a spectrum of diseases ranging from asthma and allergic bronchopulmonary aspergillosis to aspergilloma and invasive aspergillosis. Airway epithelial cells have been shown to internalize A. fumigatus conidia in vitro, but the implications of this process for pathogenesis remain unclear. We have developed a cell culture model for this interaction using the human bronchial epithelium cell line 16HBE and a transgenic A. fumigatus strain expressing green fluorescent protein (GFP). Immunofluorescent staining and nystatin protection assays indicated that cells internalized upwards of 50% of bound conidia. Using fluorescence-activated cell sorting (FACS), cells directly interacting with conidia and cells not associated with any conidia were sorted into separate samples, with an overall accuracy of 75%. Genome-wide transcriptional profiling using microarrays revealed significant responses of 16HBE cells and conidia to each other. Significant changes in gene expression were identified between cells and conidia incubated alone versus together, as well as between GFP positive and negative sorted cells. -
Phosphatidylserine, a Death Knell
Cell Death and Differentiation (2001) 8, 551 ± 563 ã 2001 Nature Publishing Group All rights reserved 1350-9047/01 $15.00 www.nature.com/cdd REVIEW Phosphatidylserine, a death knell# RA Schlegel*,1 and P Williamson2 molecules are sometimes withdrawn from the matrix and hydrolyzed to produce signaling molecules, including 1 Department of Biochemistry and Molecular Biology, Penn State University, prostaglandins, diacylglycerol and ceramides. In recent University Park, PA 16802, USA years, however, a growing body of evidence has suggested 2 Department of Biology, Amherst College, Amherst, MA 01002, USA that physical and chemical properties of the bilayer itself, such * Corresponding author: RA Schlegel, Department of Biochemistry and as the thickness of the hydrophobic core1 or local lateral Molecular Biology, 428 South Frear Laboratory, Penn State University, 2±4 University Park, PA 16802, USA. Tel: (814) 865-6974; Fax: (814) 863-7024; domains of specialized lipid composition may play E-mail: [email protected] significant roles in the assembly and organization of cellular membranes. In addition to these structural contributions to Received 30.8.00; revised 13.11.00; accepted 27.11.00 membrane function, the past few years have also seen the Edited by M Piacentini revelation that a phospholipid itself, and not a derived product, acts on the extracytosolic, external face of the plasma membrane to regulate intercellular interactions. Abstract Appreciation of this new role for phospholipids was Virtually every cell in the body restricts phosphatidylserine galvanized by the demonstration that phosphatidylserine (PS) to the inner leaflet of the plasma membrane by energy- (PS) appears on the surface of apoptotic lymphocytes and dependent transport from the outer to the inner leaflet of the contributes to their phagocytosis by activated macro- phages.5 The functional importance of the phagocytosis of bilayer. -
Nesprins: from the Nuclear Envelope and Beyond
expert reviews http://www.expertreviews.org/ in molecular medicine Nesprins: from the nuclear envelope and beyond Dipen Rajgor and Catherine M. Shanahan* Nuclear envelope spectrin-repeat proteins (Nesprins), are a novel family of nuclear and cytoskeletal proteins with rapidly expanding roles as intracellular scaffolds and linkers. Originally described as proteins that localise to the nuclear envelope (NE) and establish nuclear-cytoskeletal connections, nesprins have now been found to comprise a diverse spectrum of tissue specific isoforms that localise to multiple sub-cellular compartments. Here, we describe how nesprins are necessary in maintaining cellular architecture by acting as essential scaffolds and linkers at both the NE and other sub-cellular domains. More importantly, we speculate how nesprin mutations may disrupt tissue specific nesprin scaffolds and explain the tissue specific nature of many nesprin-associated diseases, including laminopathies. The eukaryotic cytoplasm contains three major composed of three α-helical bundles with a left- types of cytoskeletal filaments: Filamentous- handed twist, and its primary function is to actin (F-actin), microtubules (MTs) and provide docking sites for proteins and other intermediate filaments (IFs). These components higher order complexes (Refs 3, 4). Although are organised in a manner that provides the cell most SR proteins contain CHDs, some possess with an internal framework fundamental for motifs which can interact with other cytoskeletal many processes, such as controlling cellular components, allowing linkage of SR-associated shape, polarity, adhesion and migration, complexes to filamentous structures other than cytokinesis, inter- and intracellular F-actin. In addition, these motifs allow cross- Nesprins: from the nuclear envelope and beyond communication and trafficking of organelles, linking between different filaments and dynamic vesicles, proteins and RNA (Refs 1, 2). -
The Nuclear Envelope: Target and Mediator of the Apoptotic Process Liora Lindenboim1, Hila Zohar1,Howardj.Worman2 and Reuven Stein1
Lindenboim et al. Cell Death Discovery (2020) 6:29 https://doi.org/10.1038/s41420-020-0256-5 Cell Death Discovery REVIEW ARTICLE Open Access The nuclear envelope: target and mediator of the apoptotic process Liora Lindenboim1, Hila Zohar1,HowardJ.Worman2 and Reuven Stein1 Abstract Apoptosis is characterized by the destruction of essential cell organelles, including the cell nucleus. The nuclear envelope (NE) separates the nuclear interior from the cytosol. During apoptosis, the apoptotic machinery, in particular caspases, increases NE permeability by cleaving its proteins, such as those of the nuclear pore complex (NPC) and the nuclear lamina. This in turns leads to passive diffusion of cytosolic apoptogenic proteins, such as caspases and nucleases, through NPCs into the nucleus and the subsequent breakdown of the NE and destruction of the nucleus. However, NE leakiness at early stages of the apoptotic process can also occur in a caspase-independent manner, where Bax, by a non-canonical action, promotes transient and repetitive localized generation and subsequent rupture of nuclear protein-filled nuclear bubbles. This NE rupture leads to discharge of apoptogenic nuclear proteins from the nucleus to the cytosol, a process that can contribute to the death process. Therefore, the NE may play a role as mediator of cell death at early stages of apoptosis. The NE can also serve as a platform for assembly of complexes that regulate the death process. Thus, the NE should be viewed as both a mediator of the cell death process and a target. 1234567890():,; 1234567890():,; 1234567890():,; 1234567890():,; Facts redistribution of the nuclear proteins to the cytosol that might subsequently act as amplifiers of the ● The NE is an important target of the apoptotic apoptotic process. -
Knowledge Management Enviroments for High Throughput Biology
Knowledge Management Enviroments for High Throughput Biology Abhey Shah A Thesis submitted for the degree of MPhil Biology Department University of York September 2007 Abstract With the growing complexity and scale of data sets in computational biology and chemoin- formatics, there is a need for novel knowledge processing tools and platforms. This thesis describes a newly developed knowledge processing platform that is different in its emphasis on architecture, flexibility, builtin facilities for datamining and easy cross platform usage. There exist thousands of bioinformatics and chemoinformatics databases, that are stored in many different forms with different access methods, this is a reflection of the range of data structures that make up complex biological and chemical data. Starting from a theoretical ba- sis, FCA (Formal Concept Analysis) an applied branch of lattice theory, is used in this thesis to develop a file system that automatically structures itself by it’s contents. The procedure of extracting concepts from data sets is examined. The system also finds appropriate labels for the discovered concepts by extracting data from ontological databases. A novel method for scaling non-binary data for use with the system is developed. Finally the future of integrative systems biology is discussed in the context of efficiently closed causal systems. Contents 1 Motivations and goals of the thesis 11 1.1 Conceptual frameworks . 11 1.2 Biological foundations . 12 1.2.1 Gene expression data . 13 1.2.2 Ontology . 14 1.3 Knowledge based computational environments . 15 1.3.1 Interfaces . 16 1.3.2 Databases and the character of biological data .