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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
Susana Schönhuth, Collin E Beachum, Jason H Knouft, Richard L Mayden
This study represents a phylogenetic analysis of Pimephales notatus, a widely distributed North American cyprinid fish species, using one mitochondrial (cytb) and two nuclear (S7 and Rag1) genes. Despite the broad geographic distribution of this species that includes independent basins, results suggest a largely drainage-independent genetic structure. Results reveal a well-supported lineage in the Ozark Highlands, which is highly divergent from the remaining populations and may represent a long-term isolated lineage that should be considered as a separate conservation and management unit...
September 14, 2016: Zootaxa
Dror S Shouval, Amlan Biswas, Yu Hui Kang, Alexandra E Griffith, Liza Konnikova, Ivan D Mascanfroni, Naresh S Redhu, Sandra M Frei, Michael Field, Andria L Doty, Jeffrey D Goldsmith, Atul K Bhan, Anthony Loizides, Batia Weiss, Baruch Yerushalmi, Tadahiro Yanagi, Xiuli Lui, Francisco J Quintana, Aleixo M Muise, Christoph Klein, Bruce H Horwitz, Sarah C Glover, Athos Bousvaros, Scott B Snapper
IL10 receptor (IL10R)-deficient mice develop spontaneous colitis and similarly, patients with loss-of-function mutations in IL10R develop severe infant-onset inflammatory bowel disease (IBD). Loss of IL10R signaling in mouse and human macrophages is associated with increased production of interleukin 1 beta (IL1B). We demonstrated that innate immune production of IL1B mediates colitis in IL10R-deficient mice. Transfer of Il1r1(-/-) CD4(+) T cells into Rag1-/-/Il10rb-/- mice reduced the severity of their colitis (compared to mice that received CD4(+) T cells that express IL1R), accompanied by decreased production of interferon gamma, tumor necrosis factor, and IL17A...
September 27, 2016: Gastroenterology
Breda M Zimkus, Lucinda P Lawson, Michael Barej, Christopher D Barratt, Alan Channing, Katrina M Dash, J Maximilian Dehling, Louis Du Preez, Philip-Sebastian Gehring, Eli Greenbaum, Václav Gvoždík, James Harvey, Jos Kielgast, Chifundera Kusamba, Zoltán T Nagy, Maciej Pabijan, Johannes Penner, Mark-Oliver Rödel, Miguel Vences, Stefan Lötters
The Mascarene ridged frog, Ptychadena mascareniensis, is a species complex that includes numerous lineages occurring mostly in humid savannas and open forests of mainland Africa, Madagascar, the Seychelles, and the Mascarene Islands. Sampling across this broad distribution presents an opportunity to examine the genetic differentiation within this complex and to investigate how the evolution of bioclimatic niches may have shaped current biogeographic patterns. Using model-based phylogenetic methods and molecular-clock dating, we constructed a time-calibrated molecular phylogenetic hypothesis for the group based on mitochondrial 16S rRNA and cytochrome b (cytb) genes and the nuclear RAG1 gene from 173 individuals...
September 21, 2016: Molecular Phylogenetics and Evolution
M Tahara, H Tsuboi, S Segawa, H Asashima, M Iizuka-Koga, T Hirota, H Takahashi, Y Kondo, M Matsui, I Matsumoto, T Sumida
We showed recently that M3 muscarinic acetylcholine receptor (M3R)-reactive CD3(+) T cells play a pathogenic role in the development of murine autoimmune sialadenitis (MIS), which mimics Sjögren's syndrome (SS). The aim of this study was to determine the effectiveness and mechanism of action of retinoic acid-related orphan receptor-gamma t (RORγt) antagonist (A213) in MIS. Splenocytes from M3R knockout (M3R(-/-) ) mice immunized with murine M3R peptide mixture were inoculated into recombination-activating gene 1 knockout (Rag-1(-/-) ) mice (M3R(-/-) →Rag-1(-/-) ) with MIS...
September 19, 2016: Clinical and Experimental Immunology
Alex R D Delbridge, Swee Heng Milon Pang, Cassandra J Vandenberg, Stephanie Grabow, Brandon J Aubrey, Lin Tai, Marco J Herold, Andreas Strasser
Neoplastic transformation is driven by oncogenic lesions that facilitate unrestrained cell expansion and resistance to antiproliferative signals. These oncogenic DNA lesions, acquired through errors in DNA replication, gene recombination, or extrinsically imposed damage, are thought to activate multiple tumor suppressive pathways, particularly apoptotic cell death. DNA damage induces apoptosis through well-described p53-mediated induction of PUMA and NOXA. However, loss of both these mediators (even together with defects in p53-mediated induction of cell cycle arrest and cell senescence) does not recapitulate the tumor susceptibility observed in p53(-/-) mice...
September 19, 2016: Journal of Experimental Medicine
Attila Kumánovics, Yu Nee Lee, Devin W Close, Emily M Coonrod, Boglarka Ujhazi, Karin Chen, Daniel G MacArthur, Gergely Krivan, Luigi D Notarangelo, Jolan E Walter
No abstract text is available yet for this article.
September 5, 2016: Journal of Allergy and Clinical Immunology
Laura L Dickey, Colleen L Worne, Jessica L Glover, Thomas E Lane, Ryan M O'Connell
BACKGROUND: MicroRNAs (miRNAs) are noncoding RNAs that modulate cellular gene expression, primarily at the post-transcriptional level. We sought to examine the functional role of miR-155 in a model of viral-induced neuroinflammation. METHODS: Acute encephalomyelitis and immune-mediated demyelination were induced by intracranial injection with the neurotropic JHM strain of mouse hepatitis virus (JHMV) into C57BL/6 miR-155 (+/+) wildtype (WT) mice or miR-155 (-/-) mice...
2016: Journal of Neuroinflammation
Katheryn Meek, Yao Xu, Caleb Bailie, Kefei Yu, Jessica A Neal
The evidence that ATM affects resolution of RAG-induced DNA double-strand breaks is profuse and unequivocal; moreover, it is clear that the RAG complex itself cooperates (in an undetermined way) with ATM to facilitate repair of these double-strand breaks by the classical nonhomologous end-joining pathway. The mechanistic basis for the cooperation between ATM and the RAG complex has not been defined, although proposed models invoke ATM and RAG2's C terminus in maintaining the RAG postcleavage complex. In this study, we show that ATM reduces the rate of both coding and signal joining in a robust episomal assay; we suggest that this is the result of increased stability of the postcleavage complex...
August 29, 2016: Journal of Immunology: Official Journal of the American Association of Immunologists
Roberto M Barrozo, Lori M Hansen, Anna M Lam, Emma C Skoog, Miriam E Martin, Lucy P Cai, Yong Lin, Andreas Latoscha, Sebastian Suerbaum, Don R Canfield, Jay V Solnick
BACKGROUND & AIMS: Peptic ulcer disease and gastric cancer are most often caused by Helicobacter pylori strains that harbor the cag pathogenicity island (cagPAI), which encodes a type IV secretion system (T4SS) that injects the CagA oncoprotein into host cells. cagY is an essential gene in the T4SS and has an unusual DNA repeat structure that predicts in-frame insertions and deletions. These cagY recombination events typically lead to a reduction in T4SS function in mouse and primate models...
August 25, 2016: Gastroenterology
Fei Cheng, Laura Twardowski, Kurt Reifenberg, Kerstin Winter, Antje Canisius, Eva Pross, Jianglin Fan, Edgar Schmitt, Leonard D Shultz, Karl J Lackner, Michael Torzewski
This study focused on the unique properties of both the Ldlr knockout defect (closely mimicking the human situation) and the BALB/c (C) inbred mouse strain (Th-2 slanted immune response). We generated two immunodeficient strains with severe combined B- and T-cell immunodeficiency with or without a complete lack of natural killer cells to revisit the role of adaptive immune responses on atherogenesis. C-Ldlr-/- Rag1-/- mice, which show severe combined B- and T-cell immunodeficiency and C-Ldlr-/- Rag1-/- Il2rg-/- mice, which combine the T- and B-cell defect with a complete lack of natural killer cells and inactivation of multiple cytokine signalling pathways were fed an atherogenic Western type diet (WTD)...
2016: PloS One
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
Rafael Leite Dantas, Dörthe Masemann, Tanja Schied, Vera Bergmeier, Thomas Vogl, Karin Loser, Bent Brachvogel, Georg Varga, Stephan Ludwig, Viktor Wixler
We recently described an inducible human TNF transgenic mouse line (ihTNFtg) that develops a psoriasis-like arthritis after doxycycline stimulation and analyzed the pathogenesis of arthritis in detail. Here, we show that the skin phenotype of these mice is characterized by hyperproliferation and aberrant activation of keratinocytes, induction of proinflammatory cytokines, and infiltration with Th1 and Treg lymphocytes, particularly with macrophage infiltration into lesional skin, thus pointing to a psoriasis-like phenotype...
August 24, 2016: Journal of Pathology
Tami John, Jolan E Walter, Catherina Schuetz, Karin Chen, Roshini S Abraham, Carmem Bonfim, Thomas G Boyce, Avni Y Joshi, Elizabeth Kang, Beatriz Tavares Costa Carvalho, Arash Mahajerin, Diane Nugent, Geetha Puthenveetil, Amit Soni, Helen Su, Morton J Cowan, Luigi Notarangelo, David Buchbinder
The use of HLA-identical hematopoietic stem cell transplantation (HSCT) demonstrates overall survival rates greater than 75 % for T-B-NK+ severe combined immunodeficiency secondary to pathogenic mutation of recombinase activating genes 1 and 2 (RAG1/2). Limited data exist regarding the use of HSCT in patients with hypomorphic RAG variants marked by greater preservation of RAG activity and associated phenotypes such as granulomatous disease in combination with autoimmunity. We describe a 17-year-old with combined immunodeficiency and immune dysregulation characterized by granulomatous lung disease and autoimmunity secondary to compound heterozygous RAG mutations...
October 2016: Journal of Clinical Immunology
Inge Wolf, Corinne Bouquet, Fritz Melchers
While c-myc often contributes to the generation of B cell transformation, its transgenic overexpression alone does not lead to full transformation of B-lineage cells. Synergistically acting second genes must cooperate. Here, we constructed doxycycline-inducible cDNA-libraries from pre-B cell mRNA. These libraries were retrovirally transduced as single copies into single cells and overexpressed in fetal-liver-derived c-myc-overexpressing pre-B cell lines. We scored transformation by survival and/or expansion of differentiating B-lineage cells in vitro and in vivo...
August 19, 2016: European Journal of Immunology
H Y Yamada, G Kumar, Y Zhang, E Rubin, S Lightfoot, W Dai, C V Rao
Mitotic error-mediated chromosome instability (CIN) can lead to aneuploidy, chromothripsis, DNA damage and/or whole chromosome gain/loss. CIN may prompt rapid accumulation of mutations and genomic alterations. Thus, CIN can promote carcinogenesis. This CIN process results from a mutation in certain genes or environmental challenge such as smoking, and is highly prevalent in various cancers, including lung cancer. A better understanding of the effects of CIN on carcinogenesis will lead to novel methods for cancer prevention and treatment...
2016: Oncogenesis
Jun J Sato, Satoshi D Ohdachi, Lazaro M Echenique-Diaz, Rafael Borroto-Páez, Gerardo Begué-Quiala, Jorge L Delgado-Labañino, Jorgelino Gámez-Díez, José Alvarez-Lemus, Son Truong Nguyen, Nobuyuki Yamaguchi, Masaki Kita
The Cuban solenodon (Solenodon cubanus) is one of the most enigmatic mammals and is an extremely rare species with a distribution limited to a small part of the island of Cuba. Despite its rarity, in 2012 seven individuals of S. cubanus were captured and sampled successfully for DNA analysis, providing new insights into the evolutionary origin of this species and into the origins of the Caribbean fauna, which remain controversial. We conducted molecular phylogenetic analyses of five nuclear genes (Apob, Atp7a, Bdnf, Brca1 and Rag1; total, 4,602 bp) from 35 species of the mammalian order Eulipotyphla...
2016: Scientific Reports
Dane Bergstrom, Jeffrey V Leyton, Arman Zereshkian, Conrad Chan, Zhongli Cai, Raymond M Reilly
INTRODUCTION: (111)In-DTPA-NLS-CSL360 radioimmunoconjugates (RIC) recognize the overexpression of the interleukin-3 receptor α-subchain (CD123) relative to the β-subchain (CD131) on leukemia stem cells (LSC). Our aim was to study Auger electron radioimmunotherapy (RIT) of acute myeloid leukemia (AML) with (111)In-DTPA-NLS-CSL360 in non-obese diabetic severe combined immunodeficiency (NOD/SCID) mice or NOD-Rag1(null)IL2rγ(null) (NRG) mice engrafted with CD123(+) human AML-5 cells. METHODS: The toxicity of three doses of (111)In-DTPA-NLS-CSL360 (3...
October 2016: Nuclear Medicine and Biology
Chowdhury S Abdullah, Zhao Li, Xiuqing Wang, Zhu-Qiu Jin
T cell infiltration has been associated with increased coronary heart disease risk in patients with diabetes mellitus. Effect of modulation of T cell trafficking on diabetes-induced cardiac fibrosis has yet to be determined. Therefore, our aim was to investigate the circulatory T cell depletion-mediated cardioprotection in streptozotocin-induced diabetic cardiomyopathy. Fingolimod (FTY720), an immunomodulatory drug, was tested in wild-type (WT) C57BL/6 and recombination activating gene 1 (Rag1) knockout (KO) mice without mature lymphocytes in streptozotocin-induced type 1 diabetic model...
October 2016: International Immunopharmacology
Hui Yu, Victor Wei Zhang, Asbjørg Stray-Pedersen, Imelda Celine Hanson, Lisa R Forbes, M Teresa de la Morena, Ivan K Chinn, Elizabeth Gorman, Nancy J Mendelsohn, Tamara Pozos, Wojciech Wiszniewski, Sarah K Nicholas, Anne B Yates, Lindsey E Moore, Knut Erik Berge, Hanne Sorte, Diana K Bayer, Daifulah ALZahrani, Raif S Geha, Yanming Feng, Guoli Wang, Jordan S Orange, James R Lupski, Jing Wang, Lee-Jun Wong
BACKGROUND: Primary immunodeficiency diseases (PIDDs) are inherited disorders of the immune system. The most severe form, severe combined immunodeficiency (SCID), presents with profound deficiencies of T cells, B cells, or both at birth. If not treated promptly, affected patients usually do not live beyond infancy because of infections. Genetic heterogeneity of SCID frequently delays the diagnosis; a specific diagnosis is crucial for life-saving treatment and optimal management. OBJECTIVE: We developed a next-generation sequencing (NGS)-based multigene-targeted panel for SCID and other severe PIDDs requiring rapid therapeutic actions in a clinical laboratory setting...
October 2016: Journal of Allergy and Clinical Immunology
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