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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
#1
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...
February 17, 2017: Journal of Immunology: Official Journal of the American Association of Immunologists
https://www.readbyqxmd.com/read/28210382/paraneoplastic-dermatomyositis-with-cutaneous-and-myopathic-disease-responsive-to-adrenocorticotropic-hormone-therapy
#2
Marisa Wolff, Christopher Mancuso, Karan Lal, Damian Dicostanzo, Charles Gropper
Dermatomyositis is a myopathic or amyopathic autoimmune connective tissue disease that presents with classic dermatologic findings ranging from: poikilodermatous photosensitivity (shawl sign), eyelid edema and violaceous-pigmentation (heliotrope sign), lichenoid eruptions on the knuckles and elbows (Gottron's sign), periungual telangiectasias, and ragged cuticles (Samitz sign). Up to 30 percent of adult-onset cases of dermatomyositis may represent a paraneoplastic syndrome warranting a thorough work-up for malignancy...
January 2017: Journal of Clinical and Aesthetic Dermatology
https://www.readbyqxmd.com/read/28199828/hucns-sc-human-nscs-fail-to-differentiate-form-ectopic-clusters-and-provide-no-cognitive-benefits-in-a-transgenic-model-of-alzheimer-s-disease
#3
Samuel E Marsh, Stephen T Yeung, Maria Torres, Lydia Lau, Joy L Davis, Edwin S Monuki, Wayne W Poon, Mathew Blurton-Jones
Transplantation of neural stem cells (NSCs) can improve cognition in animal models of Alzheimer's disease (AD). However, AD is a protracted disorder, and prior studies have examined only short-term effects. We therefore used an immune-deficient model of AD (Rag-5xfAD mice) to examine long-term transplantation of human NSCs (StemCells Inc.; HuCNS-SCs). Five months after transplantation, HuCNS-SCs had engrafted and migrated throughout the hippocampus and exhibited no differences in survival or migration in response to β-amyloid pathology...
February 14, 2017: Stem Cell Reports
https://www.readbyqxmd.com/read/28199315/szt2-dictates-gator-control-of-mtorc1-signalling
#4
Min Peng, Na Yin, Ming O Li
Mechanistic target of rapamycin complex 1 (TORC1) integrates nutrient signals to control cell growth and organismal homeostasis across eukaryotes. The evolutionarily conserved GATOR complex regulates mTORC1 signalling through Rag GTPases, and GATOR1 displays GTPase activating protein (GAP) activity for RAGA and RAGB (RAGA/B) and GATOR2 has been proposed to be an inhibitor of GATOR1. Furthermore, the metazoan-specific SESN proteins function as guanine nucleotide dissociation inhibitors (GDIs) for RAGA/B, and interact with GATOR2 with unknown effects...
February 15, 2017: Nature
https://www.readbyqxmd.com/read/28199306/kicstor-recruits-gator1-to-the-lysosome-and-is-necessary-for-nutrients-to-regulate-mtorc1
#5
Rachel L Wolfson, Lynne Chantranupong, Gregory A Wyant, Xin Gu, Jose M Orozco, Kuang Shen, Kendall J Condon, Sabrina Petri, Jibril Kedir, Sonia M Scaria, Monther Abu-Remaileh, Wayne N Frankel, David M Sabatini
The mechanistic target of rapamycin complex 1 (mTORC1) is a central regulator of cell growth that responds to diverse environmental signals and is deregulated in many human diseases, including cancer and epilepsy. Amino acids are a key input to this system, and act through the Rag GTPases to promote the translocation of mTORC1 to the lysosomal surface, its site of activation. Multiple protein complexes regulate the Rag GTPases in response to amino acids, including GATOR1, a GTPase activating protein for RAGA, and GATOR2, a positive regulator of unknown molecular function...
February 15, 2017: Nature
https://www.readbyqxmd.com/read/28187641/cryptic-within-cryptic-genetics-morphometrics-and-bioacoustics-delimitate%C3%A2-a-new-species-of-i-eleutherodactylus-i-anura-eleutherodactylidae-from-eastern-cuba
#6
Ariel Rodríguez, Álvaro Dugo-Cota, Santiago Montero-Mendieta, Alejandro Gonzalez-Voyer, Roberto Alonso Bosch, Miguel Vences, Carles Vilà
We studied the variation in genetics, bioacustics, and morphology in Eleutherodactylus glamyrus, a regionally endemic frog species restricted to high elevations in the Sierra Maestra Massif, Western Cuba that was originally described as a cryptic species hidden under the name E. auriculatus. Genetic analysis of mtDNA sequences of the 16S and cob genes identify two allopatric and strongly supported mitochondrial clades (phylogroups) which also showed no haplotype sharing in the nuclear Rag-1 gene. Bioacustic, and morphological comparisons concordantly identify these two phylogroups as independent evolutionary lineages...
January 20, 2017: Zootaxa
https://www.readbyqxmd.com/read/28186902/a-wearable-hip-assist-robot-can-improve-gait-function-and-cardiopulmonary-metabolic-efficiency-in-elderly-adults
#7
Hwang-Jae Lee, Suhyun Lee, Won Hyuk Chang, Keehong Seo, Youngbo Shim, Byung-Ok Choi, Gyu-Ha Ryu, Yun-Hee Kim
The aims of this study were to investigate the effectiveness of a newly developed wearable hip assist robot that uses an active assist algorithm to improve gait function, muscle effort, and cardiopulmonary metabolic efficiency in elderly adults. Thirty elderly adults (15 males/15 females) participated in this study. The experimental protocol consisted of overground gait at comfortable speed under three different conditions: free gait without robot assistance, robot-assisted gait with zero torque (RAG-Z), and full robot-assisted gait (RAG)...
February 6, 2017: IEEE Transactions on Neural Systems and Rehabilitation Engineering
https://www.readbyqxmd.com/read/28181240/cytochrome-p450-genetic-variations-can-predict-mrna-expression-cyclophosphamide-4-hydroxylation-and-treatment-outcomes-in-chinese-patients-with-non-hodgkin-s-lymphoma
#8
Wenying Shu, Lingyan Chen, Xiaoye Hu, Meimei Zhang, Wensheng Chen, Lei Ma, Xiaoyan Liu, Jianing Huang, Tingyuan Pang, Jia Li, Yu Zhang
To investigate the impact of cytochrome P450 (CYP) genetic polymorphisms CYP2B6, CYP2C19, and CYP3A5 on mRNA expression, cyclophosphamide/4-hydroxycyclophosphamide pharmacokinetics, and treatment outcomes of the R-CHOP regimen (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) in Chinese patients with non-Hodgkin's lymphoma, 567 cases were investigated. Plasma concentrations of cyclophosphamide/4-hydroxycyclophosphamide were determined using liquid chromatography-tandem mass spectrometry and pharmacokinetic parameters calculated...
February 9, 2017: Journal of Clinical Pharmacology
https://www.readbyqxmd.com/read/28179379/rag1-2-induces-genomic-insertions-by-mobilizing-dna-into-rag1-2-independent-breaks
#9
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...
February 8, 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
#10
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/28142027/the-right-angular-gyrus-controls-spontaneous-eyeblink-rate-a-combined-structural-mri-and-tms-study
#11
Tamami Nakano
Spontaneous eyeblink rates vary greatly between people, from several to a few dozen blinks per minute. Nevertheless, it remains unknown which brain region controls generation of spontaneous eyeblinks. To investigate this issue, the present study examined brain anatomy, which reflects inter-individual variability in eyeblink rate using structural magnetic resonance images with voxel-based morphometry (VBM) in 57 participants. The gray matter volume of the right angular gyrus (rAG) was positively associated with an increased eyeblink rate...
January 12, 2017: Cortex; a Journal Devoted to the Study of the Nervous System and Behavior
https://www.readbyqxmd.com/read/28135253/alternative-pathway-for-the-development-of-v%C3%AE-14-nkt-cells-directly-from-cd4-cd8-thymocytes-that-bypasses-the-cd4-cd8-stage
#12
Nyambayar Dashtsoodol, Tomokuni Shigeura, Minako Aihara, Ritsuko Ozawa, Satoshi Kojo, Michishige Harada, Takaho A Endo, Takashi Watanabe, Osamu Ohara, Masaru Taniguchi
Although invariant Vα14(+) natural killer T cells (NKT cells) are thought to be generated from CD4(+)CD8(+) double-positive (DP) thymocytes, the developmental origin of CD4(-)CD8(-) double-negative (DN) NKT cells still remains unresolved. Here we provide definitive genetic evidence obtained, through studies of mice with DP-stage-specific ablation of expression of the gene encoding the recombinase component RAG-2 (Rag2) and by a fate-mapping approach, that supports the proposal of the existence of an alternative developmental pathway through which a fraction of DN NKT cells with strong T-helper-type-1 (TH1)-biased and cytotoxic characteristics develop from late DN-stage thymocytes, bypassing the DP stage...
March 2017: Nature Immunology
https://www.readbyqxmd.com/read/28134937/platelet-activating-factor-paf-receptor-as-a-promising-target-for-cancer-cell-repopulation-after-radiotherapy
#13
I A da Silva-Jr, R Chammas, A P Lepique, S Jancar
A major drawback of radiotherapy is the accelerated growth of the surviving tumor cells. Radiotherapy generates a variety of lipids that bind to the receptor for platelet-activating factor, expressed by cells in the tumor microenvironment. In the present study, using the TC-1 tumor cell line, we found that irradiation induced a twofold increase in receptor expression and generated agonists of receptor. Irradiated cells induced a 20-fold increase in live TC-1 proliferation in vitro. Furthermore, subcutaneous co-injection of irradiated TC-1 cells with TC-1 expressing luciferase (TC-1 fluc(+)) markedly increased TC-1 fluc(+) proliferation in a receptor-dependent way...
January 30, 2017: Oncogenesis
https://www.readbyqxmd.com/read/28129932/chemokine-receptor-cxcr3-deficiency-exacerbates-murine-autoimmune-cholangitis-by-promoting-pathogenic-cd8-t-cell-activation
#14
Hong-Di Ma, Wen-Tao Ma, Qing-Zhi Liu, Zhi-Bin Zhao, Mu-Zi-Ying Liu, Koichi Tsuneyama, Jin-Ming Gao, William M Ridgway, Aftab A Ansari, M Eric Gershwin, Yun-Yun Fei, Zhe-Xiong Lian
CXC Chemokine Receptor 3 (CXCR3) is functionally pleiotropic and not only plays an important role in chemotaxis, but also participates in T cell differentiation and may play a critical role in inducing and maintaining immune tolerance. These observations are particularly critical for autoimmune cholangitis in which CXCR3 positive T cells are found around the portal areas of both humans and mouse models of primary biliary cholangitis (PBC). Herein, we investigated the role of CXCR3 in the pathogenesis of autoimmune cholangitis...
January 24, 2017: Journal of Autoimmunity
https://www.readbyqxmd.com/read/28115331/capacity-of-english-nhs-hospitals-to-monitor-quality-in-infection-prevention-and-control-using-a-new-european-framework-a-multilevel-qualitative-analysis
#15
Michiyo Iwami, Raheelah Ahmad, Enrique Castro-Sánchez, Gabriel Birgand, Alan P Johnson, Alison Holmes
OBJECTIVE: (1) To assess the extent to which current English national regulations/policies/guidelines and local hospital practices align with indicators suggested by a European review of effective strategies for infection prevention and control (IPC); (2) to examine the capacity of local hospitals to report on the indicators and current use of data to inform IPC management and practice. DESIGN: A national and local-level analysis of the 27 indicators was conducted...
January 23, 2017: BMJ Open
https://www.readbyqxmd.com/read/28108557/low-level-mhc-class-ii-expression-leads-to-suboptimal-th-cell-response-increased-autoaggression-and-heightened-cytokine-inducibility
#16
Yi-Ting Chen, Yu-Chia Su, Mei-Ling Chang, Pi-Fang Tsai, John T Kung
The development and activation of MHC class II (MHC-II)-restricted CD4(+) T cells are distinct immunological processes that are strictly MHC-II-dependent. To address their relative dependence on MHC-II, we established a novel ENU-induced mutant mouse on the C57BL/6 background, named I-A(12%), with ∼8-fold reduced I-A expression on the surface of B cells, dendritic cells, cortical thymic epithelial cells, and medullary thymic epithelial cells. I-A(100%) and I-A(12%) mice are highly similar with respect to the numbers of double-positive thymocytes, CD4(+)CD8(-) T cells, regulatory T cells, CD4(+) T cell marker expression, lifespan, and Th/regulatory T cell function...
January 20, 2017: Journal of Immunology: Official Journal of the American Association of Immunologists
https://www.readbyqxmd.com/read/28089905/nudix-type-motif-2-contributes-to-cancer-proliferation-through-the-regulation-of-rag-gtpase-mediated-mammalian-target-of-rapamycin-complex-1-localization
#17
Ohman Kwon, Dongoh Kwak, Sang Hoon Ha, Hyeona Jeon, Mangeun Park, Yeonho Chang, Pann-Ghill Suh, Sung Ho Ryu
Lysosomal localization of mammalian target of rapamycin complex 1 (mTORC1) is a critical step for activation of the molecule. Rag GTPases are essential for this translocation. Here, we demonstrate that Nudix-type motif 2 (NUDT2) is a novel positive regulator of mTORC1 activation. Activation of mTORC1 is impaired in NUDT2-silenced cells. Mechanistically, NUDT2 binds to Rag GTPase and controls mTORC1 translocation to the lysosomal membrane. Furthermore, NUDT2-dependent mTORC1 regulation is critical for proliferation of breast cancer cells, as NUDT2-silenced cells arrest in G0/G1 phases...
January 13, 2017: Cellular Signalling
https://www.readbyqxmd.com/read/28070494/pure-myopathy-with-enlarged-mitochondria-associated-to-a-new-mutation-in-mtnd2-gene
#18
Alice Zanolini, Ana Potic, Franco Carrara, Eleonora Lamantea, Daria Diodato, Flavia Blasevich, Silvia Marchet, Marina Mora, Francesco Pallotti, Lucia Morandi, Massimo Zeviani, Costanza Lamperti
To date, only few mutations in the mitochondrial DNA (mtDNA)-encoded ND2 subunit of Complex I have been reported, usually presenting a severe phenotype characterized by early onset encephalomyopathy and early death. In this report, we describe a new mutation in the MTND2 gene in a 21-year-old man with a mild myopathic phenotype characterized by exercise intolerance and increased plasma lactate at rest. Electromyography and brain NMR were normal, and no cardiac involvement was present. Muscle biopsy showed a massive presence of ragged red - COX-positive fibres, with enlarged mitochondria containing osmiophilic inclusions...
March 2017: Molecular Genetics and Metabolism Reports
https://www.readbyqxmd.com/read/28034779/a-mitochondrial-membrane-protein-is-a-target-for-rice-ragged-stunt-virus-in-its-insect-vector
#19
Hai-Jian Huang, Cheng-Wen Liu, Xiang Zhou, Chuan-Xi Zhang, Yan-Yuan Bao
Rice ragged stunt virus (RRSV; Reoviridae) is exclusively transmitted by the brown planthopper Nilaparvata lugens in a persistent-propagative manner. It is understood that RNA viral proliferation is associated with the intracellular membranes of the insect host cells. However, the molecular mechanisms of the interaction between the RRSV proliferation and the intracellular membranes remain essentially unknown. It will be of great interest to determine whether RRSV protein(s) directly interact with intracellular membrane components of its host cells...
February 2, 2017: Virus Research
https://www.readbyqxmd.com/read/28002842/efficacy-of-antibody-to-pnag-against-keratitis-caused-by-fungal-pathogens
#20
Ge Zhao, Tanweer S Zaidi, Cagla Bozkurt-Guzel, Tauqeer H Zaidi, James A Lederer, Gregory P Priebe, Gerald B Pier
Purpose: Developing immunotherapies for fungal eye infections is a high priority. We analyzed fungal pathogens for expression of the surface polysaccharide, poly-N-acetyl glucosamine (PNAG), and used a mouse model of ocular keratitis caused by Aspergillus flavus, A. fumigatus, or Fusarium solani to determine if PNAG was an immunotherapy target and requirements for ancillary cellular and molecular immune effectors. Methods: Enzyme-linked immunosorbent assay (ELISA) or immunofluorescence was used to detect PNAG on fungal cells...
December 1, 2016: Investigative Ophthalmology & Visual Science
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