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Richard a flavell

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https://www.readbyqxmd.com/read/27913094/hematopoietic-stem-cell-niches-produce-lineage-instructive-signals-to-control-multipotent-progenitor-differentiation
#1
Ana Cordeiro Gomes, Takahiro Hara, Vivian Y Lim, Dietmar Herndler-Brandstetter, Erin Nevius, Tatsuki Sugiyama, Shizue Tani-Ichi, Susan Schlenner, Ellen Richie, Hans-Reimer Rodewald, Richard A Flavell, Takashi Nagasawa, Koichi Ikuta, João Pedro Pereira
Hematopoietic stem cells (HSCs) self-renew in bone marrow niches formed by mesenchymal progenitors and endothelial cells expressing the chemokine CXCL12, but whether a separate niche instructs multipotent progenitor (MPP) differentiation remains unclear. We show that MPPs resided in HSC niches, where they encountered lineage-instructive differentiation signals. Conditional deletion of the chemokine receptor CXCR4 in MPPs reduced differentiation into common lymphoid progenitors (CLPs), which decreased lymphopoiesis...
November 23, 2016: Immunity
https://www.readbyqxmd.com/read/27846608/the-dna-sensing-aim2-inflammasome-controls-radiation-induced-cell-death-and-tissue-injury
#2
Bo Hu, Chengcheng Jin, Hua-Bing Li, Jiyu Tong, Xinshou Ouyang, Naniye Malli Cetinbas, Shu Zhu, Till Strowig, Fred C Lam, Chen Zhao, Jorge Henao-Mejia, Omer Yilmaz, Katherine A Fitzgerald, Stephanie C Eisenbarth, Eran Elinav, Richard A Flavell
Acute exposure to ionizing radiation induces massive cell death and severe damage to tissues containing actively proliferating cells, including bone marrow and the gastrointestinal tract. However, the cellular and molecular mechanisms underlying this pathology remain controversial. Here, we show that mice deficient in the double-stranded DNA sensor AIM2 are protected from both subtotal body irradiation-induced gastrointestinal syndrome and total body irradiation-induced hematopoietic failure. AIM2 mediates the caspase-1-dependent death of intestinal epithelial cells and bone marrow cells in response to double-strand DNA breaks caused by ionizing radiation and chemotherapeutic agents...
November 11, 2016: Science
https://www.readbyqxmd.com/read/27846573/a-pathogenic-role-for-t-cell-derived-il-22bp-in-inflammatory-bowel-disease
#3
Penelope Pelczar, Mario Witkowski, Laura Garcia Perez, Jan Kempski, Anna G Hammel, Leonie Brockmann, Dörte Kleinschmidt, Sandra Wende, Cathleen Haueis, Tanja Bedke, Marco Witkowski, Susanne Krasemann, Stefan Steurer, Carmen J Booth, Philipp Busch, Alexandra König, Ursula Rauch, Daniel Benten, Jakob R Izbicki, Thomas Rösch, Ansgar W Lohse, Till Strowig, Nicola Gagliani, Richard A Flavell, Samuel Huber
Intestinal inflammation can impair mucosal healing, thereby establishing a vicious cycle leading to chronic inflammatory bowel disease (IBD). However, the signaling networks driving chronic inflammation remain unclear. Here we report that CD4(+) T cells isolated from patients with IBD produce high levels of interleukin-22 binding protein (IL-22BP), the endogenous inhibitor of the tissue-protective cytokine IL-22. Using mouse models, we demonstrate that IBD development requires T cell-derived IL-22BP. Lastly, intestinal CD4(+) T cells isolated from IBD patients responsive to treatment with antibodies against tumor necrosis factor-α (anti-TNF-α), the most effective known IBD therapy, exhibited reduced amounts of IL-22BP expression but still expressed IL-22...
October 21, 2016: Science
https://www.readbyqxmd.com/read/27798161/tlr8-couples-socs-1-and-restrains-tlr7-mediated-antiviral-immunity-exacerbating-west-nile-virus-infection-in-mice
#4
Amber M Paul, Dhiraj Acharya, Linda Le, Penghua Wang, Dobrivoje S Stokic, A Arturo Leis, Lena Alexopoulou, Terrence Town, Richard A Flavell, Erol Fikrig, Fengwei Bai
West Nile virus (WNV) is a neurotropic ssRNA flavivirus that can cause encephalitis, meningitis, and death in humans and mice. Human TLR7 and TLR8 and mouse TLR7 recognize viral ssRNA motifs and induce antiviral immunity. However, the role of mouse TLR8 in antiviral immunity is poorly understood. In this article, we report that TLR8-deficient (Tlr8(-/-)) mice were resistant to WNV infection compared with wild-type controls. Efficient WNV clearance and moderate susceptibility to WNV-mediated neuronal death in Tlr8(-/-) mice were attributed to overexpression of Tlr7 and IFN-stimulated gene-56 expression, whereas reduced expression of the proapoptotic gene coding Bcl2-associated X protein was observed...
December 1, 2016: Journal of Immunology: Official Journal of the American Association of Immunologists
https://www.readbyqxmd.com/read/27795421/interleukin-17a-promotes-cd8-t-cell-cytotoxicity-to-facilitate-west-nile-virus-clearance
#5
Dhiraj Acharya, Penghua Wang, Amber M Paul, Jianfeng Dai, David Gate, Jordan E Lowery, Dobrivoje S Stokic, A Arturo Leis, Richard A Flavell, Terrence Town, Erol Fikrig, Fengwei Bai
: CD8(+) T cells are crucial components of immunity and play a vital role in recovery from West Nile virus (WNV) infection. Here, we identify a previously unrecognized function of interleukin-17A (IL-17A) in inducing cytotoxic mediator gene expression and promoting CD8(+) T cell cytotoxicity against WNV infection in mice. We find that IL-17A deficient mice (Il17a(-/-)) are more susceptible to WNV infection and develop a higher viral burden compared to wild-type (WT) mice. Interestingly, the CD8(+) T cells isolated from Il17a(-/-) mice are less cytotoxic and express lower levels of cytotoxic mediator genes, which can be restored by supplying recombinant IL-17A in vitro and in vivo Importantly, treatment of WNV-infected mice with recombinant IL-17A, as late as day 6 post-infection, significantly reduces viral burden and increases survival, suggesting a therapeutic potential of IL-17A...
October 19, 2016: Journal of Virology
https://www.readbyqxmd.com/read/27723723/microenvironment-dependent-growth-of-preneoplastic-and-malignant-plasma-cells-in-humanized-mice
#6
Rituparna Das, Till Strowig, Rakesh Verma, Srinivas Koduru, Anja Hafemann, Stephanie Hopf, Mehmet H Kocoglu, Chiara Borsotti, Lin Zhang, Andrew Branagan, Elizabeth Eynon, Markus G Manz, Richard A Flavell, Madhav V Dhodapkar
Most human cancers, including myeloma, are preceded by a precursor state. There is an unmet need for in vivo models to study the interaction of human preneoplastic cells in the bone marrow microenvironment with non-malignant cells. Here, we genetically humanized mice to permit the growth of primary human preneoplastic and malignant plasma cells together with non-malignant cells in vivo. Growth was largely restricted to the bone marrow, mirroring the pattern in patients with myeloma. Xenografts captured the genomic complexity of parental tumors and revealed additional somatic changes...
November 2016: Nature Medicine
https://www.readbyqxmd.com/read/27618552/glioma-induced-inhibition-of-caspase-3-in-microglia-promotes-a-tumor-supportive-phenotype
#7
Xianli Shen, Miguel A Burguillos, Ahmed M Osman, Jeroen Frijhoff, Alejandro Carrillo-Jiménez, Sachie Kanatani, Martin Augsten, Dalel Saidi, Johanna Rodhe, Edel Kavanagh, Anthony Rongvaux, Vilma Rraklli, Ulrika Nyman, Johan Holmberg, Arne Östman, Richard A Flavell, Antonio Barragan, Jose Luis Venero, Klas Blomgren, Bertrand Joseph
Glioma cells recruit and exploit microglia (the resident immune cells of the brain) for their proliferation and invasion ability. The underlying molecular mechanism used by glioma cells to transform microglia into a tumor-supporting phenotype has remained elusive. We found that glioma-induced microglia conversion was coupled to a reduction in the basal activity of microglial caspase-3 and increased S-nitrosylation of mitochondria-associated caspase-3 through inhibition of thioredoxin-2 activity, and that inhibition of caspase-3 regulated microglial tumor-supporting function...
September 12, 2016: Nature Immunology
https://www.readbyqxmd.com/read/27617863/abc-transporters-and-nr4a1-identify-a-quiescent-subset-of-tissue-resident-memory-t-cells
#8
Chandra Sekhar Boddupalli, Shiny Nair, Simon M Gray, Heba N Nowyhed, Rakesh Verma, Joanna A Gibson, Clara Abraham, Deepak Narayan, Juan Vasquez, Catherine C Hedrick, Richard A Flavell, Kavita M Dhodapkar, Susan M Kaech, Madhav V Dhodapkar
Immune surveillance in tissues is mediated by a long-lived subset of tissue-resident memory T cells (Trm cells). A putative subset of tissue-resident long-lived stem cells is characterized by the ability to efflux Hoechst dyes and is referred to as side population (SP) cells. Here, we have characterized a subset of SP T cells (Tsp cells) that exhibit a quiescent (G0) phenotype in humans and mice. Human Trm cells in the gut and BM were enriched in Tsp cells that were predominantly in the G0 stage of the cell cycle...
October 3, 2016: Journal of Clinical Investigation
https://www.readbyqxmd.com/read/27581357/inv-16-and-npm1mut-amls-engraft-human-cytokine-knock-in-mice
#9
Jana M Ellegast, Philipp J Rauch, Larisa V Kovtonyuk, Rouven Müller, Ulrich Wagner, Yasuyuki Saito, Nicole Wildner-Verhey van Wijk, Christine Fritz, Anahita Rafiei, Veronika Lysenko, Ewa Dudkiewicz, Alexandre P Theocharides, Davide Soldini, Jeroen S Goede, Richard A Flavell, Markus G Manz
Favorable-risk human acute myeloid leukemia (AML) engrafts poorly in currently used immunodeficient mice, possibly because of insufficient environmental support of these leukemic entities. To address this limitation, we here transplanted primary human AML with isolated nucleophosmin (NPM1) mutation and AML with inv(16) in mice in which human versions of genes encoding cytokines important for myelopoiesis (macrophage colony-stimulating factor [M-CSF], interleukin-3, granulocyte-macrophage colony-stimulating factor, and thrombopoietin) were knocked into their respective mouse loci...
October 27, 2016: Blood
https://www.readbyqxmd.com/read/27562264/microbiome-ecology-of-eczema
#10
Ian D Odell, Richard A Flavell
No abstract text is available yet for this article.
2016: Nature Microbiology
https://www.readbyqxmd.com/read/27543436/peripheral-blood-cd34-cells-efficiently-engraft-human-cytokine-knock-in-mice
#11
Yasuyuki Saito, Jana M Ellegast, Anahita Rafiei, Yuanbin Song, Daniel Kull, Mathias Heikenwalder, Anthony Rongvaux, Stephanie Halene, Richard A Flavell, Markus G Manz
Human CD34(+) hematopoietic stem and progenitor cells (HSPCs) can reconstitute a human hemato-lymphoid system when transplanted into immunocompromised mice. While fetal liver- and cord blood-derived CD34(+) cells lead to high engraftment levels, engraftment of mobilized, adult donor-derived CD34(+) cells has remained poor. We generated so-called MSTRG and MISTRG hu-manized mice on a Rag2(-/-)Il2rg(-/-) background carrying a transgene for human SIRPα and human homologues of the cytokines macrophage-colony stimulating factor, thrombopoietin, with or without interleukin-3 and granulocyte-macrophage colony stimulating factor under murine promotors...
August 19, 2016: Blood
https://www.readbyqxmd.com/read/27525555/the-long-non-coding-rna-morrbid-regulates-bim-and-short-lived-myeloid-cell-lifespan
#12
Jonathan J Kotzin, Sean P Spencer, Sam J McCright, Dinesh B Uthaya Kumar, Magalie A Collet, Walter K Mowel, Ellen N Elliott, Asli Uyar, Michelle A Makiya, Margaret C Dunagin, Christian C D Harman, Anthony T Virtue, Stella Zhu, Will Bailis, Judith Stein, Cynthia Hughes, Arjun Raj, E John Wherry, Loyal A Goff, Amy D Klion, John L Rinn, Adam Williams, Richard A Flavell, Jorge Henao-Mejia
Neutrophils, eosinophils and 'classical' monocytes collectively account for about 70% of human blood leukocytes and are among the shortest-lived cells in the body. Precise regulation of the lifespan of these myeloid cells is critical to maintain protective immune responses and minimize the deleterious consequences of prolonged inflammation. However, how the lifespan of these cells is strictly controlled remains largely unknown. Here we identify a long non-coding RNA that we termed Morrbid, which tightly controls the survival of neutrophils, eosinophils and classical monocytes in response to pro-survival cytokines in mice...
August 15, 2016: Nature
https://www.readbyqxmd.com/read/27455420/apoptosis-in-response-to-microbial-infection-induces-autoreactive-th17-cells
#13
Laura Campisi, Gaetan Barbet, Yi Ding, Enric Esplugues, Richard A Flavell, J Magarian Blander
Microbial infections often precede the onset of autoimmunity. How infections trigger autoimmunity remains poorly understood. We investigated the possibility that infection might create conditions that allow the stimulatory presentation of self peptides themselves and that this might suffice to elicit autoreactive T cell responses that lead to autoimmunity. Self-reactive CD4(+) T cells are major drivers of autoimmune disease, but their activation is normally prevented through regulatory mechanisms that limit the immunostimulatory presentation of self antigens...
September 2016: Nature Immunology
https://www.readbyqxmd.com/read/27325889/gut-microbiota-translocation-to-the-pancreatic-lymph-nodes-triggers-nod2-activation-and-contributes-to-t1d-onset
#14
Frederico R C Costa, Marcela C S Françozo, Gabriela G de Oliveira, Aline Ignacio, Angela Castoldi, Dario S Zamboni, Simone G Ramos, Niels O Câmara, Marcel R de Zoete, Noah W Palm, Richard A Flavell, João S Silva, Daniela Carlos
Type 1 diabetes (T1D) is an autoimmune disease that is triggered by both genetic and environmental factors, resulting in the destruction of pancreatic β cells. The disruption of the intestinal epithelial barrier and consequent escape of microbial products may be one of these environmental triggers. However, the immune receptors that are activated in this context remain elusive. We show here that during streptozotocin (STZ)-induced T1D, the nucleotide-binding oligomerization domain containing 2 (NOD2), but not NOD1, participates in the pathogenesis of the disease by inducing T helper 1 (Th1) and Th17 cells in the pancreatic LNs (PLNs) and pancreas...
June 27, 2016: Journal of Experimental Medicine
https://www.readbyqxmd.com/read/27271566/plasticity-of-th17-cells-in-autoimmune-kidney-diseases
#15
Christian F Krebs, Jan-Eric Turner, Hans-Joachim Paust, Sonja Kapffer, Tobias Koyro, Sonja Krohn, Friederike Ufer, Manuel A Friese, Richard A Flavell, Brigitta Stockinger, Oliver M Steinmetz, Rolf A K Stahl, Samuel Huber, Ulf Panzer
The ability of CD4(+) T cells to differentiate into pathogenic Th1 and Th17 or protective T regulatory cells plays a pivotal role in the pathogenesis of autoimmune diseases. Recent data suggest that CD4(+) T cell subsets display a considerable plasticity. This plasticity seems to be a critical factor for their pathogenicity, but also for the potential transition of pathogenic effector T cells toward a more tolerogenic phenotype. The aim of the current study was to analyze the plasticity of Th17 cells in a mouse model of acute crescentic glomerulonephritis and in a mouse chronic model of lupus nephritis...
July 15, 2016: Journal of Immunology: Official Journal of the American Association of Immunologists
https://www.readbyqxmd.com/read/27249342/recent-advances-in-dynamic-m6a-rna-modification
#16
REVIEW
Guangchao Cao, Hua-Bing Li, Zhinan Yin, Richard A Flavell
The identification of m(6)A demethylases and high-throughput sequencing analysis of methylated transcriptome corroborated m(6)A RNA epigenetic modification as a dynamic regulation process, and reignited its investigation in the past few years. Many basic concepts of cytogenetics have been revolutionized by the growing understanding of the fundamental role of m(6)A in RNA splicing, degradation and translation. In this review, we summarize typical features of methylated transcriptome in mammals, and highlight the 'writers', 'erasers' and 'readers' of m(6)A RNA modification...
April 2016: Open Biology
https://www.readbyqxmd.com/read/27207805/pillars-article-the-transcription-factor-gata-3-is-necessary-and-sufficient-for-th2-cytokine-gene-expression-in-cd4-t-cells-cell-1997-89-587-596
#17
Wei-Ping Zheng, Richard A Flavell
No abstract text is available yet for this article.
June 1, 2016: Journal of Immunology: Official Journal of the American Association of Immunologists
https://www.readbyqxmd.com/read/27165847/fibroblasts-and-myofibroblasts-of-the-intestinal-lamina-propria-in-physiology-and-disease
#18
Manolis Roulis, Richard A Flavell
In this Review we summarize our current understanding of the biology of mesenchymal cells of the intestinal lamina propria focusing mainly on fibroblasts and myofibroblasts. The topics covered include 1) the embryonic origin of mesenchymal cells of the intestinal lamina propria and their heterogeneity in adults, 2) the role of the mesenchyme in intestinal development, 3) the physiological function of fibroblasts and myofibroblasts in adults as part of the intestinal stem cell niche and the mucosal immune system and 4) the involvement of fibroblasts and myofibroblasts in epithelial homeostasis upon injury and in the pathogenesis of diseases such as Inflammatory Bowel Diseases, fibrosis and cancer...
May 7, 2016: Differentiation; Research in Biological Diversity
https://www.readbyqxmd.com/read/27126747/role-of-oct-1-and-partner-proteins-in-t-cell-differentiation
#19
REVIEW
Soo Seok Hwang, Lark Kyun Kim, Gap Ryol Lee, Richard A Flavell
The understanding of CD4 T cell differentiation gives important insights into the control of immune responses against various pathogens and in autoimmune diseases. Naïve CD4 T cells become effector T cells in response to antigen stimulation in combination with various environmental cytokine stimuli. Several transcription factors and cis-regulatory regions have been identified to regulate epigenetic processes on chromatin, to allow the production of proper effector cytokines during CD4 T cell differentiation...
June 2016: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/27102485/mx1-reveals-innate-pathways-to-antiviral-resistance-and-lethal-influenza-disease
#20
Padmini S Pillai, Ryan D Molony, Kimberly Martinod, Huiping Dong, Iris K Pang, Michal C Tal, Angel G Solis, Piotr Bielecki, Subhasis Mohanty, Mark Trentalange, Robert J Homer, Richard A Flavell, Denisa D Wagner, Ruth R Montgomery, Albert C Shaw, Peter Staeheli, Akiko Iwasaki
Influenza A virus (IAV) causes up to half a million deaths worldwide annually, 90% of which occur in older adults. We show that IAV-infected monocytes from older humans have impaired antiviral interferon production but retain intact inflammasome responses. To understand the in vivo consequence, we used mice expressing a functional Mx gene encoding a major interferon-induced effector against IAV in humans. In Mx1-intact mice with weakened resistance due to deficiencies in Mavs and Tlr7, we found an elevated respiratory bacterial burden...
April 22, 2016: Science
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