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Shaozhou Zhu, Christopher D Fage, Julian D Hegemann, Andreas Mielcarek, Dushan Yan, Uwe Linne, Mohamed A Marahiel
Lasso peptides are a class of ribosomally synthesized and post-translationally modified peptides (RiPPs) with a unique lariat knot-like fold that endows them with extraordinary stability and biologically relevant activity. However, the biosynthetic mechanism of these fascinating molecules remains largely speculative. Generally, two enzymes (B for processing and C for cyclization) are required to assemble the unusual knot-like structure. Several subsets of lasso peptide gene clusters feature a "split" B protein on separate open reading frames (B1 and B2), suggesting distinct functions for the B protein in lasso peptide biosynthesis...
October 18, 2016: Scientific Reports
Nitish Badhwar, Suneet Mittal, Abdi Rasekh, Smit Vasaiwala, Dan Musat, Payam S Naeini, Qi Fang, Karin Nentwich, Thomas Deneke, Jie Chang, Dhanunjaya Lakkireddy, David Wilber, Randall J Lee
No abstract text is available yet for this article.
September 28, 2016: International Journal of Cardiology
Erin A Fender, Jawad G Kiani, David R Holmes
PURPOSE OF REVIEW: Anticoagulant therapy effectively reduces the incidence of stroke in patients with atrial fibrillation (AF) but is underutilized and frequently contraindicated. The left atrial appendage (LAA) is the primary site of thrombus formation in AF patients. Surgical and percutaneous appendage closure has been evaluated as a site-specific therapy to reduce systemic thromboembolism. RECENT FINDINGS: We will review LAA closure techniques, examine recent outcome data, and discuss the indications for, and potential complications of, each approach...
November 2016: Current Atherosclerosis Reports
Timothy R Betts, Milena Leo, Sandeep Panikker, Prapa Kanagaratnam, Michael Koa-Wing, David Wyn Davies, David Hildick-Smith, Dylan G Wynne, Oliver Ormerod, Oliver R Segal, Anthony W Chow, Derick Todd, Sandra Cabrera Gomez, Graeme J Kirkwood, David Fox, Chris Pepper, John Foran, Tom Wong
OBJECTIVES: This study aimed at assessing the feasibility and long-term efficacy of left atrial appendage occlusion (LAAO) in a "real world" setting. BACKGROUND: Although LAAO has recently emerged as an alternative to oral anticoagulants in patients with atrial fibrillation for the prevention of thromboembolic stroke, "real world" data about the procedure with different devices are lacking. METHODS: Eight centers in the United Kingdom contributed to a retrospective registry for LAAO procedures undertaken between July 2009 and November 2014...
September 21, 2016: Catheterization and Cardiovascular Interventions
Cecilia Gutierrez, Daniel G Blanchard
Atrial fibrillation is a supraventricular arrhythmia that adversely affects cardiac function and increases the risk of stroke. It is the most common arrhythmia and a major source of morbidity and mortality; its prevalence increases with age. Pulse rate is sensitive, but not specific, for diagnosis, and suspected atrial fibrillation should be confirmed with 12-lead electrocardiography. Because normal electrocardiographic findings do not rule out atrial fibrillation, home monitoring is recommended if there is clinical suspicion of arrhythmia despite normal test results...
September 15, 2016: American Family Physician
Christopher D Fage, Julian D Hegemann, Annika J Nebel, Roman M Steinbach, Shaozhou Zhu, Uwe Linne, Klaus Harms, Gert Bange, Mohamed A Marahiel
Lasso peptides are natural products that assume a unique lariat knot topology. Lasso peptide isopeptidases (IsoPs) eliminate this topology through isopeptide bond cleavage. To probe how these enzymes distinguish between substrates and hydrolyze only isopeptide bonds, we examined the structure and mechanism of a previously uncharacterized IsoP from the proteobacterium Sphingopyxis alaskensis RB2256 (SpI-IsoP). We demonstrate that SpI-IsoP efficiently and specifically linearizes the lasso peptide sphingopyxin I (SpI) and variants thereof...
October 4, 2016: Angewandte Chemie
Saeedeh Negin, Mohit B Patel, Mike Gokel, Joseph W Meisel, George W Gokel
Several N,N'-Bis(n-alkyl)-4,13-diaza-18-crown-6) lariat ethers have been found to significantly enhance the potency of rifampicin and tetracycline against E. coli when administered at levels below their minimum inhibitory concentrations (MICs). The enhancements of antibiotic potency observed for the lariat ethers range from 3- to 20- fold depending on the strain of E. coli, the antibiotic, and the lengths of the alkyl chains attached at the macroring nitrogen atoms. These lariat ethers, previously thought only to be cation carriers, form well-behaved, ion-conducting pores in soybean asolectin membranes as judged by planar bilayer conductance measurements...
September 9, 2016: Chembiochem: a European Journal of Chemical Biology
Jana Kralovicova, Igor Vorechovsky
The auxiliary factor of U2 small nuclear ribonucleoprotein (U2AF) facilitates branch point (BP) recognition and formation of lariat introns. The gene for the 35-kD subunit of U2AF gives rise to two protein isoforms (termed U2AF35a and U2AF35b) that are encoded by alternatively spliced exons 3 and Ab, respectively. The splicing recognition sequences of exon 3 are less favorable than exon Ab, yet U2AF35a expression is higher than U2AF35b across tissues. We show that U2AF35b repression is facilitated by weak, closely spaced BPs next to a long polypyrimidine tract of exon Ab...
August 26, 2016: Nucleic Acids Research
Genevieve M Gould, Joseph M Paggi, Yuchun Guo, David V Phizicky, Boris Zinshteyn, Eric T Wang, Wendy V Gilbert, David K Gifford, Christopher B Burge
Spliced messages constitute one-fourth of expressed mRNAs in the yeast Saccharomyces cerevisiae, and most mRNAs in metazoans. Splicing requires 5' splice site (5'SS), branch point (BP), and 3' splice site (3'SS) elements, but the role of the BP in splicing control is poorly understood because BP identification remains difficult. We developed a high-throughput method, Branch-seq, to map BPs and 5'SSs of isolated RNA lariats. Applied to S. cerevisiae, Branch-seq detected 76% of expressed, annotated BPs and identified a comparable number of novel BPs...
October 2016: RNA
Wojciech P Galej, Max E Wilkinson, Sebastian M Fica, Chris Oubridge, Andrew J Newman, Kiyoshi Nagai
Pre-mRNA splicing proceeds by two consecutive trans-esterification reactions via a lariat-intron intermediate. We present the 3.8 Å cryo-EM structure of the spliceosome immediately after lariat formation. The 5'-splice site is cleaved but remains close to the catalytic Mg(2+) site in the U2/U6 snRNA triplex, and the 5'-phosphate of the intron nucleotide G(+1) is linked to the branch adenosine 2'OH. The 5'-exon is held between the Prp8 amino-terminal and Linker domains, and base-pairs with U5 snRNA loop 1...
July 26, 2016: Nature
Junji Inokoshi, Nobuhiro Koyama, Midori Miyake, Yuji Shimizu, Hiroshi Tomoda
Lariatin A, an 18-residue lasso peptide encoded by the five-gene cluster larABCDE, displays potent and selective anti-mycobacterial activity. The structural feature is an N-terminal macrolactam ring, through which the C-terminal passed to form the rigid lariat-protoknot structure. In the present study, we established a convergent expression system by the strategy in which larA mutant gene-carrying plasmids were transformed into larA-deficient Rhodococcus jostii, and generated 36 lariatin variants of the precursor protein LarA to investigate the biosynthesis and the structure-activity relationships...
2016: Scientific Reports
Ruixue Wan, Chuangye Yan, Rui Bai, Gaoxingyu Huang, Yigong Shi
Each cycle of pre-messenger RNA splicing, carried out by the spliceosome, comprises two sequential transesterification reactions, which result in the removal of an intron and the joining of two exons. Here we report an atomic structure of a catalytic step I spliceosome (known as the C complex) from Saccharomyces cerevisiae, as determined by cryo-electron microscopy at an average resolution of 3.4 angstroms. In the structure, the 2'-OH of the invariant adenine nucleotide in the branch point sequence (BPS) is covalently joined to the phosphate at the 5' end of the 5' splice site (5'SS), forming an intron lariat...
August 26, 2016: Science
Randall J Lee
No abstract text is available yet for this article.
May 23, 2016: JACC. Cardiovascular Interventions
Carola Gianni, Luigi Di Biase, Chintan Trivedi, Sanghamitra Mohanty, Yalçın Gökoğlan, Mahmut F Güneş, Rong Bai, Amin Al-Ahmad, J David Burkhardt, Rodney P Horton, Andrew K Krumerman, Eugen C Palma, Miguel Valderrábano, Douglas Gibson, Matthew J Price, Andrea Natale
OBJECTIVES: The aim of this study was to evaluate the incidence and clinical implications of leaks (acute incomplete occlusion, early and late reopenings) following LAA ligation with the LARIAT device. BACKGROUND: Percutaneous LAA ligation with the LARIAT device may represent an alternative for stroke prevention in high-risk patients with atrial fibrillation with contraindications to oral anticoagulation. METHODS: This was a retrospective, multicenter study of 98 consecutive patients undergoing successful LAA ligation with the LARIAT device...
May 23, 2016: JACC. Cardiovascular Interventions
Krzysztof Bartus, Sameer Gafoor, David Tschopp, John P Foran, Roland Tilz, Tom Wong, Dhanunjaya Lakkireddy, Horst Sievert, Randall J Lee
BACKGROUND: The purpose of the study was to determine the efficacy and safety of left atrial appendage (LAA) closure with a micropuncture pericardial access approach and the new LARIAT(+) suture delivery device. METHODS: Seventy-two patients with atrial fibrillation were enrolled to undergo telescopic micropuncture pericardial access and percutaneous ligation of the LAA with the LARIAT(+) device. LAA closure was confirmed with transesophageal echocardiography (TEE) and contrast fluoroscopy immediately, then with TEE at 30days and 90days post-LAA ligation...
July 15, 2016: International Journal of Cardiology
Jean-Baptiste Fourmann, Olexandr Dybkov, Dmitry E Agafonov, Marcel J Tauchert, Henning Urlaub, Ralf Ficner, Patrizia Fabrizio, Reinhard Lührmann
The DEAH-box NTPase Prp43 and its cofactors Ntr1 and Ntr2 form the NTR complex and are required for disassembling intron-lariat spliceosomes (ILS) and defective earlier spliceosomes. However, the Prp43 binding site in the spliceosome and its target(s) are unknown. We show that Prp43 fused to Ntr1's G-patch motif (Prp43_Ntr1GP) is as efficient as the NTR in ILS disassembly, yielding identical dissociation products and recognizing its natural ILS target even in the absence of Ntr1's C-terminal-domain (CTD) and Ntr2...
2016: ELife
Mai Khanh Nguyen, Cha Yeon Kim, Jin Man Kim, Byung Ouk Park, Sangkyu Lee, Hyerim Park, Won Do Heo
Intracellular membrane trafficking, which is involved in diverse cellular processes, is dynamic and difficult to study in a spatiotemporal manner. Here we report an optogenetic strategy, termed light-activated reversible inhibition by assembled trap of intracellular membranes (IM-LARIAT), that uses various Rab GTPases combined with blue-light-induced hetero-interaction between cryptochrome 2 and CIB1. In this system, illumination induces a rapid and reversible intracellular membrane aggregation that disrupts the dynamics and functions of the targeted membrane...
June 2016: Nature Chemical Biology
Karen Massel, Jordan R Silke, Linda Bonen
Trans-splicing of discontinuous introns in plant mitochondria requires the assembly of independently-transcribed precursor RNAs into splicing-competent structures, and they are expected to be excised as Y-branched molecules ("broken lariats") because these introns belong to the group II ribozyme family. We now demonstrate that this is just one of several trans-splicing pathways for wheat mitochondrial nad1 intron 4 and nad5 intron 2; they also use a hydrolytic pathway and the liberated 5'-half-intron linear molecules are unexpectedly abundant in the RNA population...
May 2016: Mitochondrion
Hyerim Park, Sangkyu Lee, Won Do Heo
Optogenetic modules that use genetically encoded elements to control protein function in response to light allow for precise spatiotemporal modulation of signaling pathways. As one of optical approaches, LARIAT (Light-Activated Reversible Inhibition by Assembled Trap) is a unique light-inducible inhibition system that reversibly sequesters target proteins into clusters, generated by multimeric proteins and a blue light-induced heterodimerization module. Here we present a method based on LARIAT for optical inhibition of targets in living mammalian cells...
2016: Methods in Molecular Biology
Susovan Jana, Vallabh Suresh, Salvatore D Lepore
The syntheses of various lariat ethers including several not previously reported and their efficient purification are presented. The synthesis route brings together reactions from a variety of previous works leading to a robust and generalized approach to these C-pivot lariats. The main steps are condensation of functionalized diols with pentaethylene glycol ditosylate in the presence of potassium as a templating cation. Purification of the final products was achieved without chromatography by extracting from an aqueous potassium hydroxide solution...
September 2015: Synlett: Accounts and Rapid Communications in Synthetic Organic Chemistry
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