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V(d)J recombination

S Sheludiakov, J Ahokas, J Järvinen, D Zvezdov, L Lehtonen, O Vainio, S Vasiliev, D M Lee, V V Khmelenko
We report on a study of the exchange tunneling reaction D + HD → D2 + H in a pure solid HD matrix and in a D2 matrix with a 0.23% HD admixture at temperatures between 130 mK and 1.5 K. We found that the exchange reaction rates, kexHD ∼ 3 × 10(-27) cm(3) s(-1) in the pure HD matrix, and kexD2 = 9(4) × 10(-28) cm(3) s(-1) in the D2 matrix, are nearly independent of temperature within this range. This confirms the quantum tunnelling nature of these reactions, and their ability to proceed at temperatures down to absolute zero...
October 18, 2016: Physical Chemistry Chemical Physics: PCCP
G N Nguyen, L A George, J I Siner, R J Davidson, C B Zander, X L Zheng, V R Arruda, R M Camire, D E Sabatino
BACKGROUND: The major challenge for developing gene-based therapies for hemophilia A is that human factor VIII (hFVIII) has intrinsic properties that result in inefficient biosynthesis. During intracellular processing, hFVIII is predominantly cleaved at a Paired basic Amino acid Cleaving Enzyme (PACE) or furin cleavage site to yield a heterodimer that is the major form of secreted protein. Previous studies with B-domain deleted (BDD) canine FVIII and hFVIII-R1645H, both differing from hFVIII by a single amino acid at this site, suggested that these proteins are secreted mainly in a single polypeptide chain (SC) form and exhibit enhanced function...
October 17, 2016: Journal of Thrombosis and Haemostasis: JTH
V M Koladia, J D Faris, J K Richards, R S Brueggeman, S Chao, T L Friesen
A CIho 5791 × Tifang recombinant inbred mapping population was developed and used to identify major dominant resistance genes on barley chromosomes 6H and 3H in CI5791 and on 3H in Tifang. The barley line CIho 5791 confers high levels of resistance to Pyrenophora teres f. teres, causal agent of net form net blotch (NFNB), with few documented isolates overcoming this resistance. Tifang barley also harbors resistance to P. teres f. teres which was previously shown to localize to barley chromosome 3H. A CIho 5791 × Tifang F6 recombinant inbred line (RIL) population was developed using single seed descent...
October 12, 2016: TAG. Theoretical and Applied Genetics. Theoretische und Angewandte Genetik
Mansoor R Mirza, Bradley J Monk, Jørn Herrstedt, Amit M Oza, Sven Mahner, Andrés Redondo, Michel Fabbro, Jonathan A Ledermann, Domenica Lorusso, Ignace Vergote, Noa E Ben-Baruch, Christian Marth, Radosław Mądry, René D Christensen, Jonathan S Berek, Anne Dørum, Anna V Tinker, Andreas du Bois, Antonio González-Martín, Philippe Follana, Benedict Benigno, Per Rosenberg, Lucy Gilbert, Bobbie J Rimel, Joseph Buscema, John P Balser, Shefali Agarwal, Ursula A Matulonis
Background Niraparib is an oral poly(adenosine diphosphate [ADP]-ribose) polymerase (PARP) 1/2 inhibitor that has shown clinical activity in patients with ovarian cancer. We sought to evaluate the efficacy of niraparib versus placebo as maintenance treatment for patients with platinum-sensitive, recurrent ovarian cancer. Methods In this randomized, double-blind, phase 3 trial, patients were categorized according to the presence or absence of a germline BRCA mutation (gBRCA cohort and non-gBRCA cohort) and the type of non-gBRCA mutation and were randomly assigned in a 2:1 ratio to receive niraparib (300 mg) or placebo once daily...
October 7, 2016: New England Journal of Medicine
Satish K Tadi, Carine Tellier-Lebègue, Clément Nemoz, Pascal Drevet, Stéphane Audebert, Sunetra Roy, Katheryn Meek, Jean-Baptiste Charbonnier, Mauro Modesti
In mammalian cells, classical non-homologous end joining (c-NHEJ) is critical for DNA double-strand break repair induced by ionizing radiation and during V(D)J recombination in developing B and T lymphocytes. Recently, PAXX was identified as a c-NHEJ core component. We report here that PAXX-deficient cells exhibit a cellular phenotype uncharacteristic of a deficiency in c-NHEJ core components. PAXX-deficient cells display normal sensitivity to radiomimetic drugs, are proficient in transient V(D)J recombination assays, and do not shift toward higher micro-homology usage in plasmid repair assays...
October 4, 2016: Cell Reports
Jennifer Zagelbaum, Noriko Shimazaki, Zitadel Anne Esguerra, Go Watanabe, Michael R Lieber, Eli Rothenberg
Single-molecule FRET (smFRET) and single-molecule colocalization (smCL) assays have allowed us to observe the recombination-activating gene (RAG) complex reaction mechanism in real time. Our smFRET data have revealed distinct bending modes at recombination signal sequence (RSS)-conserved regions before nicking and synapsis. We show that high mobility group box 1 (HMGB1) acts as a cofactor in stabilizing conformational changes at the 12RSS heptamer and increasing RAG1/2 binding affinity for 23RSS. Using smCL analysis, we have quantitatively measured RAG1/2 dwell time on 12RSS, 23RSS, and non-RSS DNA, confirming a strict RSS molecular specificity that was enhanced in the presence of a partner RSS in solution...
October 4, 2016: Proceedings of the National Academy of Sciences of the United States of America
Sandhya R Pulivarthy, Mattia Lion, Guray Kuzu, Adam G W Matthews, Mark L Borowsky, John Morris, Robert E Kingston, Jonathan H Dennis, Michael Y Tolstorukov, Marjorie A Oettinger
We show that the physical distribution of nucleosomes at antigen receptor loci is subject to regulated cell type-specific and lineage-specific positioning and correlates with the accessibility of these gene segments to recombination. At the Ig heavy chain locus (IgH), a nucleosome in pro-B cells is generally positioned over each IgH variable (VH) coding segment, directly adjacent to the recombination signal sequence (RSS), placing the RSS in a position accessible to the recombination activating gene (RAG) recombinase...
October 3, 2016: Proceedings of the National Academy of Sciences of the United States of America
H Kamimura, R C Gouveia, S C Carrocine, L D Souza, A D Rodrigues, M D Teodoro, G E Marques, E R Leite, A J Chiquito
Indium phosphide nanowires with a single crystalline zinc-blend core and polycrystalline/amorphous shell were grown from a reliable route without the use of hazardous precursors. The nanowires are composed by a crystalline core covered by a polycrystalline shell, presenting typical lengths larger than 10 μm and diameters of 80-90 nm. Raman spectra taken from as-grown nanowires exhibited asymmetric line shapes with broadening towards higher wave numbers which can be attributed to phonon localization effects...
November 30, 2016: Journal of Physics. Condensed Matter: An Institute of Physics Journal
B Caputo, V Pichler, E Mancini, M Pombi, J L Vicente, J Dinis, K Steen, V Petrarca, A Rodrigues, J Pinto, A Della Torre, D Weetman
Speciation with gene flow may be aided by reduced recombination helping to build linkage between genes involved in the early stages of reproductive isolation. Reduced recombination on chromosome-X has been implicated in speciation within the Anopheles gambiae complex, species of which represent the major Afrotropical malaria vectors. The most recently diverged, morphologically-indistinguishable, species-pair, An. gambiae and An. coluzzii, ubiquitously display a 'genomic island of divergence' spanning over 4Mb from chromosome-X centromere, which represents a particularly promising candidate region for reproductive isolation genes, in addition to containing the diagnostic markers used to distinguish the species...
September 23, 2016: Molecular Ecology
Tamar Harel, Wan Hee Yoon, Caterina Garone, Shen Gu, Zeynep Coban-Akdemir, Mohammad K Eldomery, Jennifer E Posey, Shalini N Jhangiani, Jill A Rosenfeld, Megan T Cho, Stephanie Fox, Marjorie Withers, Stephanie M Brooks, Theodore Chiang, Lita Duraine, Serkan Erdin, Bo Yuan, Yunru Shao, Elie Moussallem, Costanza Lamperti, Maria A Donati, Joshua D Smith, Heather M McLaughlin, Christine M Eng, Magdalena Walkiewicz, Fan Xia, Tommaso Pippucci, Pamela Magini, Marco Seri, Massimo Zeviani, Michio Hirano, Jill V Hunter, Myriam Srour, Stefano Zanigni, Richard Alan Lewis, Donna M Muzny, Timothy E Lotze, Eric Boerwinkle, Richard A Gibbs, Scott E Hickey, Brett H Graham, Yaping Yang, Daniela Buhas, Donna M Martin, Lorraine Potocki, Claudio Graziano, Hugo J Bellen, James R Lupski
ATPase family AAA-domain containing protein 3A (ATAD3A) is a nuclear-encoded mitochondrial membrane protein implicated in mitochondrial dynamics, nucleoid organization, protein translation, cell growth, and cholesterol metabolism. We identified a recurrent de novo ATAD3A c.1582C>T (p.Arg528Trp) variant by whole-exome sequencing (WES) in five unrelated individuals with a core phenotype of global developmental delay, hypotonia, optic atrophy, axonal neuropathy, and hypertrophic cardiomyopathy. We also describe two families with biallelic variants in ATAD3A, including a homozygous variant in two siblings, and biallelic ATAD3A deletions mediated by nonallelic homologous recombination (NAHR) between ATAD3A and gene family members ATAD3B and ATAD3C...
October 6, 2016: American Journal of Human Genetics
Donna Lee M Dinnes, Melanie Y White, Maaike Kockx, Mathew Traini, Victar Hsieh, Mi-Jurng Kim, Liming Hou, Wendy Jessup, Kerry-Anne Rye, Morten Thaysen-Andersen, Stuart J Cordwell, Leonard Kritharides
Apolipoprotein A-I (apoA-I) is the major component of HDL and central to the ability of HDL to stimulate ATP-binding cassette transporter A1 (ABCA1)-dependent, antiatherogenic export of cholesterol from macrophage foam cells, a key player in the pathology of atherosclerosis. Cell-mediated modifications of apoA-I such as chlorination, nitration, oxidation, and proteolysis can impair its antiatherogenic function, although it is unknown if macrophages themselves contribute to such modifications. To investigate this, human monocyte-derived macrophages (HMDM) were incubated with human apoA-I under conditions used to induce cholesterol export...
September 14, 2016: FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology
Robert Hastings, Carin de Villiers, Charlotte Hooper, Liz Ormondroyd, Alistair Pagnamenta, Stefano Lise, Silvia Salatino, Samantha J L Knight, Jenny C Taylor, Kate L Thomson, Linda Arnold, Spyros D Chatziefthimiou, Petr V Konarev, Matthias Wilmanns, Elisabeth Ehler, Andrea Ghisleni, Mathias Gautel, Edward Blair, Hugh Watkins, Katja Gehmlich
BACKGROUND: -High throughput next generation sequencing techniques have made whole genome sequencing accessible in clinical practice, however, the abundance of variation in the human genomes makes the identification of a disease-causing mutation on a background of benign rare variants challenging. METHODS AND RESULTS: -Here we combine whole genome sequencing with linkage analysis in a three-generation family affected by cardiomyopathy with features of autosomal dominant left-ventricular non-compaction cardiomyopathy...
September 13, 2016: Circulation. Cardiovascular Genetics
Liang Chen, Lijuan Zhao, Frederick W Alt, Michael S Krangel
Chromatin looping mediated by the CCCTC binding factor (CTCF) regulates V(D)J recombination at Ag receptor loci. CTCF-mediated looping can influence recombination signal sequence (RSS) accessibility by regulating enhancer activation of germline promoters. CTCF-mediated looping has also been shown to limit directional tracking of the RAG recombinase along chromatin, and to regulate long-distance interactions between RSSs, independent of the RAG recombinase. However, in all prior instances in which CTCF-mediated looping was shown to influence V(D)J recombination, it was not possible to fully resolve the relative contributions to the V(D)J recombination phenotype of changes in accessibility, RAG tracking, and RAG-independent long-distance interactions...
September 9, 2016: Journal of Immunology: Official Journal of the American Association of Immunologists
Divya Punwani, Misako Kawahara, Jason Yu, Ukina Sanford, Sushmita Roy, Kiran Patel, Denise A Carbonaro, Andrea D Karlen, Sara Khan, Kenneth G Cornetta, Michael Rothe, Axel Schambach, Donald B Kohn, Harry L Malech, R Scott McIvor, Jennifer M Puck, Morton J Cowan
During B and T lymphocyte maturation, V(D)J recombination is initiated by creation of DNA double-strand breaks. Artemis is an exonuclease essential for their subsequent repair by non-homologous end-joining. Mutations in DCLRE1C, the gene encoding Artemis, cause T-B-NK+ severe combined immunodeficiency (ART-SCID) and also confer heightened sensitivity to ionizing radiation and alkylating chemotherapy. Although allogeneic hematopoietic cell transplantation (HCT) can treat ART-SCID, conditioning regimens are poorly tolerated, leading to early mortality and/or late complications, including short stature, endocrinopathies, and dental aplasia...
September 9, 2016: Human Gene Therapy
Ming Tian, Cheng Cheng, Xuejun Chen, Hongying Duan, Hwei-Ling Cheng, Mai Dao, Zizhang Sheng, Michael Kimble, Lingshu Wang, Sherry Lin, Stephen D Schmidt, Zhou Du, M Gordon Joyce, Yiwei Chen, Brandon J DeKosky, Yimin Chen, Erica Normandin, Elizabeth Cantor, Rita E Chen, Nicole A Doria-Rose, Yi Zhang, Wei Shi, Wing-Pui Kong, Misook Choe, Amy R Henry, Farida Laboune, Ivelin S Georgiev, Pei-Yi Huang, Suvi Jain, Andrew T McGuire, Eric Georgeson, Sergey Menis, Daniel C Douek, William R Schief, Leonidas Stamatatos, Peter D Kwong, Lawrence Shapiro, Barton F Haynes, John R Mascola, Frederick W Alt
The design of immunogens that elicit broadly reactive neutralizing antibodies (bnAbs) has been a major obstacle to HIV-1 vaccine development. One approach to assess potential immunogens is to use mice expressing precursors of human bnAbs as vaccination models. The bnAbs of the VRC01-class derive from the IGHV1-2 immunoglobulin heavy chain and neutralize a wide spectrum of HIV-1 strains via targeting the CD4 binding site of the envelope glycoprotein gp120. We now describe a mouse vaccination model that allows a germline human IGHV1-2(∗)02 segment to undergo normal V(D)J recombination and, thereby, leads to the generation of peripheral B cells that express a highly diverse repertoire of VRC01-related receptors...
September 8, 2016: Cell
L G Holinka, E Largo, D P Gladue, V O'Donnell, G R Risatti, J L Nieva, M V Borca
: E2, the major envelope glycoprotein of classical swine fever virus (CSFV), is involved in several critical virus functions including cell attachment, host range susceptibility, and virulence in natural hosts. Functional structural analysis of E2 based on Wimley-White interfacial hydrophobicity distribution predicted the involvement of a loop (residues 864-881) stabilized by a disulfide bond ((869)CKWGGNWTCV(878), named FPII) in establishing interactions with the host cell membrane. This loop further contains an (872)GG(873) dipeptide, and two aromatic residues ((871)W and (875)W) accessible to solvent...
September 7, 2016: Journal of Virology
Vipul Kumar, Frederick W Alt, Richard L Frock
Classical nonhomologous end joining (C-NHEJ) is a major mammalian DNA double-strand break (DSB) repair pathway. Core C-NHEJ factors, such as XRCC4, are required for joining DSB intermediates of the G1 phase-specific V(D)J recombination reaction in progenitor lymphocytes. Core factors also contribute to joining DSBs in cycling mature B-lineage cells, including DSBs generated during antibody class switch recombination (CSR) and DSBs generated by ionizing radiation. The XRCC4-like-factor (XLF) C-NHEJ protein is dispensable for V(D)J recombination in normal cells, but because of functional redundancy, it is absolutely required for this process in cells deficient for the ataxia telangiectasia-mutated (ATM) DSB response factor...
September 20, 2016: Proceedings of the National Academy of Sciences of the United States of America
Chloé Lescale, Hélène Lenden Hasse, Andrew N Blackford, Gabriel Balmus, Joy J Bianchi, Wei Yu, Léa Bacoccina, Angélique Jarade, Christophe Clouin, Rohan Sivapalan, Bernardo Reina-San-Martin, Stephen P Jackson, Ludovic Deriano
Paralog of XRCC4 and XLF (PAXX) is a member of the XRCC4 superfamily and plays a role in nonhomologous end-joining (NHEJ), a DNA repair pathway critical for lymphocyte antigen receptor gene assembly. Here, we find that the functions of PAXX and XLF in V(D)J recombination are masked by redundant joining activities. Thus, combined PAXX and XLF deficiency leads to an inability to join RAG-cleaved DNA ends. Additionally, we demonstrate that PAXX function in V(D)J recombination depends on its interaction with Ku...
September 13, 2016: Cell Reports
R J Bevacqua, R Fernandez-Martín, V Savy, N G Canel, M I Gismondi, W A Kues, D F Carlson, S C Fahrenkrug, H Niemann, O A Taboga, S Ferraris, D F Salamone
The recently developed engineered nucleases, such as zinc-finger nucleases, transcription activator-like effector nucleases, and clustered regularly interspaced short palindromic repeat (CRISPR)/CRISPR-associated nuclease (Cas) 9, provide new opportunities for gene editing in a straightforward manner. However, few reports are available regarding CRISPR application and efficiency in cattle. Here, the CRISPR/Cas9 system was used with the aim of inducing knockout and knock-in alleles of the bovine PRNP gene, responsible for mad cow disease, both in bovine fetal fibroblasts and in IVF embryos...
November 2016: Theriogenology
Katarina Ochodnicka-Mackovicova, Mahnoush Bahjat, Chiel Maas, Amélie van der Veen, Timon A Bloedjes, Alexander M de Bruin, Harmen van Andel, Carol E Schrader, Rudi W Hendriks, Els Verhoeyen, Richard J Bende, Carel J M van Noesel, Jeroen E J Guikema
The recombination activating gene (RAG) 1 and RAG2 protein complex introduces DNA breaks at Tcr and Ig gene segments that are required for V(D)J recombination in developing lymphocytes. Proper regulation of RAG1/2 expression safeguards the ordered assembly of Ag receptors and the development of lymphocytes, while minimizing the risk for collateral damage. The ataxia telangiectasia mutated (ATM) kinase is involved in the repair of RAG1/2-mediated DNA breaks and prevents their propagation. The simultaneous occurrence of RAG1/2-dependent and -independent DNA breaks in developing lymphocytes exposed to genotoxic stress increases the risk for aberrant recombinations...
October 1, 2016: Journal of Immunology: Official Journal of the American Association of Immunologists
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