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Richard a flavell

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...
October 10, 2016: Nature Medicine
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
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
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 mostly used immuno-deficient mice, possibly due to insufficient environmental support of these leukemic entities. To address this limitation, we here transplanted primary human AML with isolated NPM1 mutation and AML with inv(16) in mice in which human versions of genes encoding cytokines important for myelopoiesis (M-CSF, IL-3, GM-CSF, Thrombopoietin) were knocked into their respective mouse loci. NPM1(mut) AML engrafted with higher efficacy in cytokine knock-in mice and showed a trend towards higher bone marrow engraftment levels in comparison to NSG mice...
August 31, 2016: Blood
Ian D Odell, Richard A Flavell
No abstract text is available yet for this article.
2016: Nature Microbiology
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
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 ~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 while minimizing the deleterious consequences of prolonged inflammation. However, how the lifespan of these cells is strictly controlled remains largely unknown. Here we identify a novel long non-coding RNA (lncRNA) that we termed Morrbid, which tightly controls the survival of neutrophils, eosinophils and 'classical' monocytes in response to pro-survival cytokines...
August 15, 2016: Nature
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
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
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
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
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
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
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
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
Pamela Y Chan, Eugenio A Carrera Silva, Dimitri De Kouchkovsky, Leonel D Joannas, Liming Hao, Donglei Hu, Scott Huntsman, Celeste Eng, Paula Licona-Limón, Jason S Weinstein, De'Broski R Herbert, Joseph E Craft, Richard A Flavell, Silvia Repetto, Jorge Correale, Esteban G Burchard, Dara G Torgerson, Sourav Ghosh, Carla V Rothlin
Host responses against metazoan parasites or an array of environmental substances elicit type 2 immunity. Despite its protective function, type 2 immunity also drives allergic diseases. The mechanisms that regulate the magnitude of the type 2 response remain largely unknown. Here, we show that genetic ablation of a receptor tyrosine kinase encoded byTyro3in mice or the functional neutralization of its ortholog in human dendritic cells resulted in enhanced type 2 immunity. Furthermore, the TYRO3 agonist PROS1 was induced in T cells by the quintessential type 2 cytokine, interleukin-4...
April 1, 2016: Science
Jijun Cheng, Christine A Roden, Wen Pan, Shu Zhu, Anna Baccei, Xinghua Pan, Tingting Jiang, Yuval Kluger, Sherman M Weissman, Shangqin Guo, Richard A Flavell, Ye Ding, Jun Lu
Clustered regularly-interspaced palindromic repeats (CRISPR)-based genetic screens using single-guide-RNA (sgRNA) libraries have proven powerful to identify genetic regulators. Applying CRISPR screens to interrogate functional elements in noncoding regions requires generating sgRNA libraries that are densely covering, and ideally inexpensive, easy to implement and flexible for customization. Here we present a Molecular Chipper technology for generating dense sgRNA libraries for genomic regions of interest, and a proof-of-principle screen that identifies novel cis-regulatory domains for miR-142 biogenesis...
2016: Nature Communications
Jens Geginat, Paola Larghi, Moira Paroni, Giulia Nizzoli, Alessandra Penatti, Massimiliano Pagani, Nicola Gagliani, Pierluigi Meroni, Sergio Abrignani, Richard A Flavell
Interleukin-10 (IL-10) is known to be a tolerogenic cytokine since it inhibits pro-inflammatory cytokine production and T cell stimulatory capacities of myeloid cells, such as macrophages and dendritic cells. In particular, it has a non-redundant tolerogenic role in intestinal immune homeostasis, since mice and patients with genetic defects in the IL-10/IL-10R pathway develop spontaneously colitis in the presence of a normal intestinal flora. However, IL-10 is also a growth and differentiation factor for B-cells, can promote autoantibody production and has consequently a pathogenic role in systemic lupus erythematosus...
August 2016: Cytokine & Growth Factor Reviews
Shu Zhu, Geng Wang, Xuqiu Lei, Richard A Flavell
Toll-Like Receptors (TLRs) play critical roles in the early innate immune response to invading pathogens by sensing microorganisms; a number of accessory molecules have been shown to assist microbial recognition by TLRs. In a recent paper in Cell Research, Yang et al. demonstrate that Mex3B is associated with TLR3 in the endosomes and promotes dsRNA binding and proteolytic processing of TLR3, suggesting that Mex3B acts as a coreceptor of TLR3 in response to dsRNA.
April 2016: Cell Research
Hoe C-Y Lee, Helen Flavell, Dave Parsons, Richard Parsons, Torbjorn Falkmer
In this paper, an approach to teaching occupational therapy students how to create orthoses, whilst at the same time developing higher-order critical thinking, reflective, and clinical reasoning skills is described. The scaffolded nature of the learning activities, incorporating Kolb's reflective learning cycle, was used to support students' capacity for clinical reasoning and better prepare them for clinical placement. The peer-assessment element was also designed to support the experiential learning by allowing students to test their evaluation of hand orthoses, compare their assessment with an expert's, and identify areas for improvement...
2016: Journal of Allied Health
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