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V(d)J recombination

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https://www.readbyqxmd.com/read/28346544/epigenetic-silencing-of-v-d-j-recombination-is-a-major-determinant-for-selective-differentiation-of-mucosal-associated-invariant-t-cells-from-induced-pluripotent-stem-cells
#1
Yutaka Saito, Chie Sugimoto, Toutai Mituyama, Hiroshi Wakao
Mucosal-associated invariant T cells (MAITs) are innate-like T cells that play a pivotal role in the host defense against infectious diseases, and are also implicated in autoimmune diseases, metabolic diseases, and cancer. Recent studies have shown that induced pluripotent stem cells (iPSCs) derived from MAITs selectively redifferentiate into MAITs without altering their antigen specificity. Such a selective differentiation is a prerequisite for the use of MAITs in cell therapy and/or regenerative medicine...
2017: PloS One
https://www.readbyqxmd.com/read/28339253/distinct-evolutions-of-weyl-fermion-quasiparticles-and-fermi-arcs-with-bulk-band-topology-in-weyl-semimetals
#2
N Xu, G Autès, C E Matt, B Q Lv, M Y Yao, F Bisti, V N Strocov, D Gawryluk, E Pomjakushina, K Conder, N C Plumb, M Radovic, T Qian, O V Yazyev, J Mesot, H Ding, M Shi
The Weyl semimetal phase is a recently discovered topological quantum state of matter characterized by the presence of topologically protected degeneracies near the Fermi level. These degeneracies are the source of exotic phenomena, including the realization of chiral Weyl fermions as quasiparticles in the bulk and the formation of Fermi arc states on the surfaces. Here, we demonstrate that these two key signatures show distinct evolutions with the bulk band topology by performing angle-resolved photoemission spectroscopy, supported by first-principles calculations, on transition-metal monophosphides...
March 10, 2017: Physical Review Letters
https://www.readbyqxmd.com/read/28301581/assessing-tn5-and-sleeping-beauty-for-transpositional-transgenesis-by-cytoplasmic-injection-into-bovine-and-ovine-zygotes
#3
R J Bevacqua, R Fernandez-Martin, N G Canel, A Gibbons, D Texeira, F Lange, G Vans Landschoot, V Savy, O Briski, M I Hiriart, E Grueso, Z Ivics, O Taboga, W A Kues, S Ferraris, D F Salamone
Transgenic domestic animals represent an alternative to bioreactors for large-scale production of biopharmaceuticals and could also provide more accurate biomedical models than rodents. However, their generation remains inefficient. Recently, DNA transposons allowed improved transgenesis efficiencies in mice and pigs. In this work, Tn5 and Sleeping Beauty (SB) transposon systems were evaluated for transgenesis by simple cytoplasmic injection in livestock zygotes. In the case of Tn5, the transposome complex of transposon nucleic acid and Tn5 protein was injected...
2017: PloS One
https://www.readbyqxmd.com/read/28289136/estrogen-modulates-mesenchymal-epidermal-interactions-in-the-adult-nipple
#4
Hsing-Jung Wu, Ji Won Oh, Dan F Spandau, Sunil Tholpady, Jesus Diaz, Laura J Schroeder, Carlos D Offutt, Adam B Glick, Maksim V Plikus, Sachiko Koyama, John Foley
Maintenance of specialized epidermis requires signals from the underlying mesenchyme; however, specific pathways involved remain to be identified. By recombining cells from ventral skin of the K14-PTHrP transgenic mice with those from wild-type, we show that transgenic stroma is sufficient to reprogram wild-type keratinocytes into nipple-like epidermis. To identify candidate nipple-specific signaling factors, we compared gene expression signatures of sorted Pdgfrα-positive ventral K14-PTHrP and wild-type fibroblasts, identifying differentially-expressed transcripts of the WNT, HGF, TGFβ, IGF, BMP, FGF and estrogen signaling...
March 13, 2017: Development
https://www.readbyqxmd.com/read/28256716/assessing-microenvironment-immunogenicity-using-tumor-specimen-exomes-co-detection-of-tcr-%C3%AE-%C3%AE-v-d-j-recombinations-correlates-with-pd-1-expression
#5
Yaping N Tu, Wei Lue Tong, Mohammad D Samy, John M Yavorski, Minjung Kim, George Blanck
T-cell receptor (TcR) recombinations can be recovered from tumor specimen, whole exome (WXS) files. However, it is not yet clear how these recombinations represent lymphocytes or an anti-tumor immune response. Here we report the identification of productive TcR-β recombinations in WXS files representing primary and metastatic melanoma. The recombinations are identifiable in about 20% of the cancer genome atlas melanoma samples. This frequency of detection is lower than the frequency of TcR-α VJ recombinations, consistent with the occurrence of biallelic TcR-α recombinations and possibly consistent with fact that only one junctional recombination is required for TcR-α whereas two recombinations are required to form a TcR-β gene...
March 3, 2017: International Journal of Cancer. Journal International du Cancer
https://www.readbyqxmd.com/read/28255168/mapping-sites-of-herpes-simplex-virus-type-1-glycoprotein-d-that-permit-insertions-and-impact-gd-and-gb-receptors-usage
#6
Qing Fan, Sarah Kopp, Sarah A Connolly, William J Muller, Richard Longnecker
Glycoprotein D (gD) of herpes simplex virus type 1 (HSV-1) is one of four glycoproteins essential for HSV entry and cell fusion. The purpose of this study was to determine the plasticity of gD to tolerate insertion or deletion mutations and to construct an oncolytic HSV-1 that utilizes the disialoganglioside GD2 as a HSV-1 entry receptor. We found that the N-terminus of gD tolerates long insertions, whereas residues adjacent to the gD Ig-like V-type core tolerated shorter insertions (up to 15 amino acids), but not greater than 60 amino acids...
March 3, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28245243/serelaxin-as-a-potential-treatment-for-renal-dysfunction-in-cirrhosis-preclinical-evaluation-and-results-of-a-randomized-phase-2-trial
#7
Victoria K Snowdon, Neil J Lachlan, Anna M Hoy, Patrick W F Hadoke, Scott I Semple, Dilip Patel, Will Mungall, Timothy J Kendall, Adrian Thomson, Ross J Lennen, Maurits A Jansen, Carmel M Moran, Antonella Pellicoro, Prakash Ramachandran, Isaac Shaw, Rebecca L Aucott, Thomas Severin, Rajnish Saini, Judy Pak, Denise Yates, Neelesh Dongre, Jeremy S Duffield, David J Webb, John P Iredale, Peter C Hayes, Jonathan A Fallowfield
BACKGROUND: Chronic liver scarring from any cause leads to cirrhosis, portal hypertension, and a progressive decline in renal blood flow and renal function. Extreme renal vasoconstriction characterizes hepatorenal syndrome, a functional and potentially reversible form of acute kidney injury in patients with advanced cirrhosis, but current therapy with systemic vasoconstrictors is ineffective in a substantial proportion of patients and is limited by ischemic adverse events. Serelaxin (recombinant human relaxin-2) is a peptide molecule with anti-fibrotic and vasoprotective properties that binds to relaxin family peptide receptor-1 (RXFP1) and has been shown to increase renal perfusion in healthy human volunteers...
February 2017: PLoS Medicine
https://www.readbyqxmd.com/read/28244489/chromosome-choice-for-initiation-of-v-d-j-recombination-is-not-governed-by-genomic-imprinting
#8
Claudia Gebert, Lauren Correia, Zhenhu Li, Howard T Petrie, Paul E Love, Karl Pfeifer
V-(D)-J recombination generates the antigen receptor diversity necessary for immune cell function, while allelic exclusion ensures that each cell expresses a single antigen receptor. V-(D)-J recombination of the Ig, Tcrb, Tcrg and Tcrd antigen receptor genes is ordered and sequential so that only one allele generates a productive rearrangement. The mechanism controlling sequential rearrangement of antigen receptor genes, in particular how only one allele is selected to initiate recombination while at least temporarily leaving the other intact, remains unresolved...
February 28, 2017: Immunology and Cell Biology
https://www.readbyqxmd.com/read/28223274/long-term-responders-on-olaparib-maintenance-in-high-grade-serous-ovarian-cancer-clinical-and-molecular-characterization
#9
Stephanie Lheureux, Zhongwu Lai, Brian A Dougherty, Sarah Runswick, Darren Hodgson, Kirsten M Timms, Jerry S Lanchbury, Stanley B Kaye, Charlie Gourley, David D L Bowtell, Elise C Kohn, Clare L Scott, Ursula A Matulonis, Tony Panzarella, Katherine Karakasis, Julia V Burnier, Blake Gilks, Mark J O'Connor, Jane D Robertson, Jonathan Ledermann, J Carl Barrett, Tony W Ho, Amit M Oza
PURPOSE: Maintenance therapy with olaparib has improved progression-free survival in women with high-grade serous ovarian cancer (HGSOC), particularly those harboring BRCA1/2 mutations. The objective of this study was to characterize long-term (LT) versus short-term (ST) responders to olaparib. EXPERIMENTAL DESIGN: A comparative molecular analysis of Study 19 (NCT00753545), a randomized Phase II trial assessing olaparib maintenance after response to platinum-based chemotherapy in HGSOC, was conducted...
February 21, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/28220631/treatment-of-bleeding-episodes-with-recombinant-factor-viii-fc-fusion-protein-in-a-long-study-subjects-with-severe-haemophilia-a
#10
A D Shapiro, J N Mahlangu, D Perry, J Pasi, D V Quon, P Chowdary, E Tsao, S Li, A Innes, G F Pierce, G A Allen
INTRODUCTION: The Phase 3 A-LONG study demonstrated the safety and efficacy of rFVIIIFc for the control and prevention of bleeding episodes in severe haemophilia A. AIM: To describe the treatment of bleeding episodes with rFVIIIFc in the A-LONG study. METHODS: A-LONG subjects (<1 IU dL(-1) endogenous FVIII) were treated with individualized prophylaxis (Arm 1), weekly prophylaxis (Arm 2) or episodic treatment (Arm 3). Information recorded for each bleeding episode included type, location and dose to treat the episode...
February 20, 2017: Haemophilia: the Official Journal of the World Federation of Hemophilia
https://www.readbyqxmd.com/read/28216420/evaluation-of-rag1-mutations-in-an-adult-with-combined-immunodeficiency-and-progressive-multifocal-leukoencephalopathy
#11
Claudia Schröder, Niklas Thomas Baerlecken, Ulrich Pannicke, Thilo Dörk, Torsten Witte, Roland Jacobs, Matthias Stoll, Klaus Schwarz, Bodo Grimbacher, Reinhold E Schmidt, Faranaz Atschekzei
Here we describe novel mutations in recombination activation gene 1 (RAG1) in a compound heterozygous male patient with combined T and B cell immunodeficiency (CID). Clinical manifestations besides antibody deficiency included airway infections, granulomatosis and autoimmune features. He died at the age of 37 due to PML caused by JC virus infection. By targeted next-generation sequencing we detected post mortem in this patient three mutations in RAG1. One allele harbored two novel mutations (c.1123C>G, p...
February 20, 2017: Clinical Immunology: the Official Journal of the Clinical Immunology Society
https://www.readbyqxmd.com/read/28213501/immature-lymphocytes-inhibit-rag1-and-rag2-transcription-and-v-d-j-recombination-in-response-to-dna-double-strand-breaks
#12
Megan R Fisher, Adrian Rivera-Reyes, Noah B Bloch, David G Schatz, Craig H Bassing
Mammalian cells have evolved a common DNA damage response (DDR) that sustains cellular function, maintains genomic integrity, and suppresses malignant transformation. In pre-B cells, DNA double-strand breaks (DSBs) induced at Igκ loci by the Rag1/Rag2 (RAG) endonuclease engage this DDR to modulate transcription of genes that regulate lymphocyte-specific processes. We previously reported that RAG DSBs induced at one Igκ allele signal through the ataxia telangiectasia mutated (ATM) kinase to feedback-inhibit RAG expression and RAG cleavage of the other Igκ allele...
April 1, 2017: Journal of Immunology: Official Journal of the American Association of Immunologists
https://www.readbyqxmd.com/read/28193549/identification-of-rare-hiv-1-group-n-hbv-ae-and-htlv-3-strains-in-rural-south-cameroon
#13
M A Rodgers, A S Vallari, B Harris, J Yamaguchi, V Holzmayer, K Forberg, M G Berg, J Kenmenge, C Ngansop, B Awazi, D Mbanya, L Kaptue, C Brennan, G Cloherty, N Ndembi
Surveillance of emerging viral variants is critical to ensuring that blood screening and diagnostic tests detect all infections regardless of strain or geographic location. In this study, we conducted serological and molecular surveillance to monitor the prevalence and diversity of HIV, HBV, and HTLV in South Cameroon. The prevalence of HIV was 8.53%, HBV was 10.45%, and HTLV was 1.04% amongst study participants. Molecular characterization of 555 HIV-1 specimens identified incredible diversity, including 7 subtypes, 12 CRFs, 6 unclassified, 24 Group O and 2 Group N infections...
February 10, 2017: Virology
https://www.readbyqxmd.com/read/28179379/rag1-2-induces-genomic-insertions-by-mobilizing-dna-into-rag1-2-independent-breaks
#14
Philipp C Rommel, Thiago Y Oliveira, Michel C Nussenzweig, Davide F Robbiani
The RAG recombinase (RAG1/2) plays an essential role in adaptive immunity by mediating V(D)J recombination in developing lymphocytes. In contrast, aberrant RAG1/2 activity promotes lymphocyte malignancies by causing chromosomal translocations and DNA deletions at cancer genes. RAG1/2 can also induce genomic DNA insertions by transposition and trans-V(D)J recombination, but only few such putative events have been documented in vivo. We used next-generation sequencing techniques to examine chromosomal rearrangements in primary murine B cells and discovered that RAG1/2 causes aberrant insertions by releasing cleaved antibody gene fragments that subsequently reintegrate into DNA breaks induced on a heterologous chromosome...
March 6, 2017: Journal of Experimental Medicine
https://www.readbyqxmd.com/read/28174273/h3k4me3-induces-allosteric-conformational-changes-in-the-dna-binding-and-catalytic-regions-of-the-v-d-j-recombinase
#15
John Bettridge, Chan Hyun Na, Akhilesh Pandey, Stephen Desiderio
V(D)J recombination is initiated by the recombination-activating gene (RAG) recombinase, consisting of RAG-1 and RAG-2 subunits. The susceptibility of gene segments to cleavage by RAG is associated with histone modifications characteristic of active chromatin, including trimethylation of histone H3 at lysine 4 (H3K4me3). Binding of H3K4me3 by a plant homeodomain (PHD) in RAG-2 stimulates substrate binding and catalysis, which are functions of RAG-1. This has suggested an allosteric mechanism in which information regarding occupancy of the RAG-2 PHD is transmitted to RAG-1...
February 7, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28150718/distinct-requirement-of-runx-complexes-for-tcr%C3%AE-enhancer-activation-at-distinct-developmental-stages
#16
Wooseok Seo, Sawako Muroi, Kaori Akiyama, Ichiro Taniuchi
A TCRβ enhancer, known as the Eβ enhancer, plays a critical role in V(D)J recombination and transcription of the Tcrb gene. However, the coordinated action of trans-acting factors in the activation of Eβ during T cell development remains uncharacterized. Here, we characterized the roles of Runx complexes in the regulation of the Eβ function. A single mutation at one of the two Runx binding motifs within the Eβ severely impaired Tcrb activation at the initiation phase in immature thymocytes. However, TCRβ expression level in mature thymocytes that developed under such a single Runx site mutation was similar to that of the control...
February 2, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28133799/human-ig-knockin-mice-to-study-the-development-and-regulation-of-hiv-1-broadly-neutralizing-antibodies
#17
REVIEW
Laurent Verkoczy, Frederick W Alt, Ming Tian
A major challenge for HIV-1 vaccine research is developing a successful immunization approach for inducing broadly neutralizing antibodies (bnAbs). A key shortcoming in meeting this challenge has been the lack of animal models capable of identifying impediments limiting bnAb induction and ranking vaccine strategies for their ability to promote bnAb development. Since 2010, immunoglobulin knockin (KI) technology, involving inserting functional rearranged human variable exons into the mouse IgH and IgL loci has been used to express bnAbs in mice...
January 2017: Immunological Reviews
https://www.readbyqxmd.com/read/28126552/design-and-expression-of-recombinant-toxins-from-mexican-scorpions-of-the-genus-centruroides-for-production-of-antivenoms
#18
J M Jiménez-Vargas, V Quintero-Hernández, L González-Morales, E Ortiz, L D Possani
This manuscript describes the design of plasmids containing the genes coding for four main mammalian toxins of scorpions from the genus Centruroides (C.) of Mexico. The genes that code for toxin 2 of C. noxius (Cn2), toxin 2 from C. suffusus (Css2) and toxins 1 and 2 from C. limpidus (Cll1 and Cll2) were included into individual plasmids carrying the genetic construction for expression of fusion proteins containing a leader peptide (pelB) that directs the expressed protein to the bacterial periplasm, a carrier protein (thioredoxin), the cleavage site for enterokinase, the chosen toxin and a poly-histidine tag (6xHis-tag) for purification of the hybrid protein by immobilized metal ion affinity chromatography after expression in Escherichia coli strain BL21 (DE3)...
January 23, 2017: Toxicon: Official Journal of the International Society on Toxinology
https://www.readbyqxmd.com/read/28105679/robust-immunoglobulin-class-switch-recombination-and-end-joining-in-parp9-deficient-mice
#19
Isabelle Robert, Léa Gaudot, Jose Yelamos, Aurélia Noll, Heng-Kuan Wong, Françoise Dantzer, Valérie Schreiber, Bernardo Reina-San-Martin
To mount highly specific and adapted immune responses, B lymphocytes assemble and diversify their antibody repertoire through mechanisms involving the formation of programmed DNA damage. Immunoglobulin class switch recombination (CSR) is triggered by DNA lesions induced by activation-induced cytidine deaminase, which are processed to double-stranded DNA break (DSB) intermediates. These DSBs activate the cellular DNA damage response and enroll numerous DNA repair factors, involving Poly(ADP-ribose) polymerases Parp1, Parp2 and Parp3 to promote appropriate DNA repair and efficient long-range recombination...
January 20, 2017: European Journal of Immunology
https://www.readbyqxmd.com/read/28089565/fgf21-is-an-exocrine-pancreas-secretagogue
#20
Katie C Coate, Genaro Hernandez, Curtis A Thorne, Shengyi Sun, Thao D V Le, Kevin Vale, Steven A Kliewer, David J Mangelsdorf
The metabolic stress hormone FGF21 is highly expressed in exocrine pancreas, where its levels are increased by refeeding and chemically induced pancreatitis. However, its function in the exocrine pancreas remains unknown. Here, we show that FGF21 stimulates digestive enzyme secretion from pancreatic acinar cells through an autocrine/paracrine mechanism that requires signaling through a tyrosine kinase receptor complex composed of an FGF receptor and β-Klotho. Mice lacking FGF21 accumulate zymogen granules and are susceptible to pancreatic ER stress, an effect that is reversed by administration of recombinant FGF21...
February 7, 2017: Cell Metabolism
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