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Hyunje G Cho, Katherine J Ransohoff, Lingyao Yang, Haley Hedlin, Themistocles Assimes, Jiali Han, Marcia Stefanick, Jean Y Tang, Kavita Y Sarin
BACKGROUND: Single-nucleotide polymorphisms (SNPs) associated with melanoma have been identified though genome-wide association studies (GWASs). However, the combined impact of these SNPs on melanoma development remains unclear, particularly in post-menopausal women who carry lower melanoma risk. OBJECTIVE: To examine the contribution of a combined polygenic risk score on melanoma development in post-menopausal women. METHODS: Genetic risk scores (GRS) were calculated using 21 GWAS-significant SNPs...
February 27, 2018: Journal of the American Academy of Dermatology
Julia D Ransohoff, Azadeh Nikfarjam, Erik Jones, Brian Loew, Bernice Y Kwong, Kavita Y Sarin, Nigam H Shah
No abstract text is available yet for this article.
March 1, 2018: JAMA Oncology
Krista J Spiller, Clark R Restrepo, Tahiyana Khan, Myrna A Dominique, Terry C Fang, Rebecca G Canter, Christopher J Roberts, Kelly R Miller, Richard M Ransohoff, John Q Trojanowski, Virginia M-Y Lee
Though motor neurons selectively degenerate in amyotrophic lateral sclerosis, other cell types are likely involved in this disease. We recently generated rNLS8 mice in which human TDP-43 (hTDP-43) pathology could be reversibly induced in neurons and expected that microglia would contribute to neurodegeneration. However, only subtle microglial changes were detected during disease in the spinal cord, despite progressive motor neuron loss; microglia still reacted to inflammatory triggers in these mice. Notably, after hTDP-43 expression was suppressed, microglia dramatically proliferated and changed their morphology and gene expression profiles...
February 20, 2018: Nature Neuroscience
Atsuko Katsumoto, Aline S Miranda, Oleg Butovsky, Antônio L Teixeira, Richard M Ransohoff, Bruce T Lamb
BACKGROUND: Traumatic brain injury (TBI) is a critical public health and socio-economic problem worldwide. A growing body of evidence supports the involvement of inflammatory events in TBI. It has been reported that resident microglia and infiltrating monocytes promote an inflammatory reaction that leads to neuronal death and eventually behavioral and cognitive impairment. Currently, there is no effective treatment for TBI and the development of new therapeutic strategies is a scientific goal of highest priority...
January 30, 2018: Journal of Neuroinflammation
Chad A Tagge, Andrew M Fisher, Olga V Minaeva, Amanda Gaudreau-Balderrama, Juliet A Moncaster, Xiao-Lei Zhang, Mark W Wojnarowicz, Noel Casey, Haiyan Lu, Olga N Kokiko-Cochran, Sudad Saman, Maria Ericsson, Kristen D Onos, Ronel Veksler, Vladimir V Senatorov, Asami Kondo, Xiao Z Zhou, Omid Miry, Linnea R Vose, Katisha R Gopaul, Chirag Upreti, Christopher J Nowinski, Robert C Cantu, Victor E Alvarez, Audrey M Hildebrandt, Erich S Franz, Janusz Konrad, James A Hamilton, Ning Hua, Yorghos Tripodis, Andrew T Anderson, Gareth R Howell, Daniela Kaufer, Garth F Hall, Kun P Lu, Richard M Ransohoff, Robin O Cleveland, Neil W Kowall, Thor D Stein, Bruce T Lamb, Bertrand R Huber, William C Moss, Alon Friedman, Patric K Stanton, Ann C McKee, Lee E Goldstein
The mechanisms underpinning concussion, traumatic brain injury, and chronic traumatic encephalopathy, and the relationships between these disorders, are poorly understood. We examined post-mortem brains from teenage athletes in the acute-subacute period after mild closed-head impact injury and found astrocytosis, myelinated axonopathy, microvascular injury, perivascular neuroinflammation, and phosphorylated tau protein pathology. To investigate causal mechanisms, we developed a mouse model of lateral closed-head impact injury that uses momentum transfer to induce traumatic head acceleration...
January 18, 2018: Brain: a Journal of Neurology
Jonathan Hummel, Mark Pagkaliwangan, Xhorxhi Gjoka, Terence Davidovits, Rick Stock, Thomas Ransohoff, Rene Gantier, Mark Schofield
The biopharmaceutical industry is evolving in response to changing market conditions, including increasing competition and growing pressures to reduce costs. Single-use technologies and continuous bioprocessing have attracted attention as potential facilitators of cost-optimized manufacturing for monoclonal antibodies. While disposable bioprocessing has been adopted at many scales of manufacturing, continuous bioprocessing has yet to reach the same level of implementation. In this study, the cost of goods of Pall Life Science's integrated, continuous bioprocessing platform was modeled, along with that of purification processes in stainless-steel and single-use batch formats...
January 17, 2018: Biotechnology Journal
Xingyu Wang, Wanming Zhao, Richard M Ransohoff, Lan Zhou
Acute skeletal muscle injury repair requires an adequate inflammatory response predominated by macrophage infiltration. We studied the activation of infiltrating macrophages by analyzing the expression of M1/M2 signature genes. Most of the intramuscular macrophages were Ly6Chi at day 1 after BaCl2 injection, while many were Ly6Clo at day 3. Ly6Chi macrophages at day 1 expressed a high level of both M1 and M2 genes, and the Ly6Chi and Ly6Clo macrophages at day 3 expressed a similar level of many M1/M2 genes...
January 4, 2018: Journal of Neuroimmunology
Fumitaka Shimizu, Richard M Ransohoff
No abstract text is available yet for this article.
December 5, 2017: Oncotarget
Julia D Ransohoff, Yuning Wei, Paul A Khavari
Long intergenic non-coding RNA (lincRNA) genes have diverse features that distinguish them from mRNA-encoding genes and exercise functions such as remodelling chromatin and genome architecture, RNA stabilization and transcription regulation, including enhancer-associated activity. Some genes currently annotated as encoding lincRNAs include small open reading frames (smORFs) and encode functional peptides and thus may be more properly classified as coding RNAs. lincRNAs may broadly serve to fine-tune the expression of neighbouring genes with remarkable tissue specificity through a diversity of mechanisms, highlighting our rapidly evolving understanding of the non-coding genome...
March 2018: Nature Reviews. Molecular Cell Biology
Shane M Bemiller, Tyler J McCray, Kevin Allan, Shane V Formica, Guixiang Xu, Gina Wilson, Olga N Kokiko-Cochran, Samuel D Crish, Cristian A Lasagna-Reeves, Richard M Ransohoff, Gary E Landreth, Bruce T Lamb
BACKGROUND: Genetic variants of the Triggering Receptor Expressed on Myeloid Cells-2 (TREM2) confer increased risk of developing late-onset Alzheimer's Disease (LOAD) and other neurodegenerative disorders. Recent studies provided insight into the multifaceted roles of TREM2 in regulating extracellular β-amyloid (Aβ) pathology, myeloid cell accumulation, and inflammation observed in AD, yet little is known regarding the role of TREM2 in regulating intracellular microtubule associated protein tau (MAPT; tau) pathology in neurodegenerative diseases and in AD, in particular...
October 16, 2017: Molecular Neurodegeneration
Hansruedi Mathys, Chinnakkaruppan Adaikkan, Fan Gao, Jennie Z Young, Elodie Manet, Martin Hemberg, Philip L De Jager, Richard M Ransohoff, Aviv Regev, Li-Huei Tsai
Microglia, the tissue-resident macrophages in the brain, are damage sensors that react to nearly any perturbation, including neurodegenerative diseases such as Alzheimer's disease (AD). Here, using single-cell RNA sequencing, we determined the transcriptome of more than 1,600 individual microglia cells isolated from the hippocampus of a mouse model of severe neurodegeneration with AD-like phenotypes and of control mice at multiple time points during progression of neurodegeneration. In this neurodegeneration model, we discovered two molecularly distinct reactive microglia phenotypes that are typified by modules of co-regulated type I and type II interferon response genes, respectively...
October 10, 2017: Cell Reports
Geert D'Haens, Severine Vermeire, Harald Vogelsang, Matthieu Allez, Pierre Desreumaux, Andre Van Gossum, William J Sandborn, Daniel C Baumgart, Richard M Ransohoff, Gail M Comer, Alaa Ahmad, Fabio Cataldi, John Cheng, Robert Clare, Kenneth J Gorelick, Annamarie Kaminski, Vivek Pradhan, Sunday Rivers, Matthew O Sikpi, Yanhua Zhang, Mina Hassan-Zahraee, Walter Reinisch, Olaf Stuve
Background & Aims: Progressive multifocal leukoencephalopathy, a brain infection associated with anti-integrin drugs that inhibit lymphocyte translocation from bloodstream to tissue, can be fatal. Decreased central-nervous-system immune surveillance leading to this infection has been reported in patients with multiple sclerosis or Crohn's disease treated with anti-integrin antibody natalizumab. PF-00547659 is an investigational human monoclonal antibody for inflammatory bowel disease targeted against α4β7-mucosal addressin cell-adhesion molecule-1 (the integrin ligand selectively expressed in the gut)...
September 16, 2017: Journal of Crohn's & Colitis
Julia D Ransohoff, Bernice Y Kwong
The identification of oncogenic drivers of liquid tumors has led to the rapid development of targeted agents with distinct cutaneous adverse event (AE) profiles. The diagnosis and management of these skin toxicities has motivated a novel partnership between dermatologists and oncologists in developing supportive oncodermatology clinics. In this article we review the current state of knowledge of clinical presentation, mechanisms, and management of the most common and significant cutaneous AEs observed during treatment with targeted therapies for hematologic and lymphoid malignancies...
December 2017: Clinical Lymphoma, Myeloma & Leukemia
Olga N Kokiko-Cochran, Maha Saber, Shweta Puntambekar, Shane Michael Bemiller, Atsuko Katsumoto, Yu-Shang Lee, Kiran Bhaskar, Richard M Ransohoff, Bruce T Lamb
TBI induces widespread neuroinflammation and accumulation of microtubule associated protein tau (MAPT) - two key pathological features of tauopathies. This study sought to characterize the microglial/macrophage response to TBI in genomic-based MAPT transgenic mice in a Mapt knockout background (called hTau). Two-month-old hTau and age-matched control male and female mice received a single lateral fluid percussion TBI or sham injury. Separate groups of mice were aged to an acute (3 days post-injury [DPI]) or chronic (135 DPI) post-injury time point...
August 31, 2017: Journal of Neurotrauma
Mitsuhiko Katoh, Bao Wu, Huy Bang Nguyen, Truc Quynh Thai, Ryo Yamasaki, Haiyan Lu, Anna M Rietsch, Musab M Zorlu, Youichi Shinozaki, Yurika Saitoh, Sei Saitoh, Takashi Sakoh, Kazuhiro Ikenaka, Schuichi Koizumi, Richard M Ransohoff, Nobuhiko Ohno
Microglia are the resident macrophages of the central nervous system and play complex roles in the milieu of diseases including the primary diseases of myelin. Although mitochondria are critical for cellular functions and survival in the nervous system, alterations in and the roles of mitochondrial dynamics and associated signaling in microglia are still poorly understood. In the present study, by combining immunohistochemistry and 3D ultrastructural analyses, we show that mitochondrial fission/fusion in reactive microglia is differentially regulated from that in monocyte-derived macrophages and the ramified microglia of normal white matter in myelin disease models...
July 10, 2017: Scientific Reports
Fumitaka Shimizu, Kristin L Schaller, Gregory P Owens, Anne C Cotleur, Debra Kellner, Yukio Takeshita, Birgit Obermeier, Thomas J Kryzer, Yasuteru Sano, Takashi Kanda, Vanda A Lennon, Richard M Ransohoff, Jeffrey L Bennett
Neuromyelitis optica (NMO) is an inflammatory disorder mediated by antibodies to aquaporin-4 (AQP4) with prominent blood-brain barrier (BBB) breakdown in the acute phase of the disease. Anti-AQP4 antibodies are produced mainly in the periphery, yet they target the astrocyte perivascular end feet behind the BBB. We reasoned that an endothelial cell-targeted autoantibody might promote BBB transit of AQP4 antibodies and facilitate NMO attacks. Using monoclonal recombinant antibodies (rAbs) from patients with NMO, we identified two that strongly bound to the brain microvascular endothelial cells (BMECs)...
July 5, 2017: Science Translational Medicine
Shankar Sadasivan, Bridgett Sharp, Stacey Schultz-Cherry, Richard Jay Smeyne
Central Nervous System inflammation has been implicated in neurodegenerative disorders including Parkinson's disease (Ransohoff, Science 353: 777-783, 2016; Kannarkat et al. J. Parkinsons Dis. 3: 493-514, 2013). Here, we examined if the H1N1 influenza virus (Studahl et al. Drugs 73: 131-158, 2013) could synergize with the parkinsonian toxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (Jackson-Lewis et al. in Mark LeDoux (ed) Movement Disorders: Genetics and Models: 287-306, Elsevier, 2015) to induce a greater microglial activation and loss of substantia nigra pars compacta dopaminergic neurons than either insult alone...
2017: NPJ Parkinson's Disease
Chenhui Wang, Cun-Jin Zhang, Bradley N Martin, Katarzyna Bulek, Zizhen Kang, Junjie Zhao, Guanglin Bian, Julie A Carman, Ji Gao, Ashok Dongre, Haibo Xue, Stephen D Miller, Youcun Qian, Dolores Hambardzumyan, Tom Hamilton, Richard M Ransohoff, Xiaoxia Li
NOTCH1 signalling contributes to defective remyelination by impairing differentiation of oligodendrocyte progenitor cells (OPCs). Here we report that IL-17 stimulation induces NOTCH1 activation in OPCs, contributing to Th17-mediated demyelinating disease. Mechanistically, IL-17R interacts with NOTCH1 via the extracellular domain, which facilitates the cleavage of NOTHC1 intracellular domain (NICD1). IL-17-induced NOTCH1 activation results in the interaction of IL-17R adaptor Act1 with NICD1, followed by the translocation of the Act1-NICD1 complex into the nucleus...
May 31, 2017: Nature Communications
David Gosselin, Dylan Skola, Nicole G Coufal, Inge R Holtman, Johannes C M Schlachetzki, Eniko Sajti, Baptiste N Jaeger, Carolyn O'Connor, Conor Fitzpatrick, Martina P Pasillas, Monique Pena, Amy Adair, David D Gonda, Michael L Levy, Richard M Ransohoff, Fred H Gage, Christopher K Glass
Microglia play essential roles in central nervous system (CNS) homeostasis and influence diverse aspects of neuronal function. However, the transcriptional mechanisms that specify human microglia phenotypes are largely unknown. We examined the transcriptomes and epigenetic landscapes of human microglia isolated from surgically resected brain tissue ex vivo and after transition to an in vitro environment. Transfer to a tissue culture environment resulted in rapid and extensive down-regulation of microglia-specific genes that were induced in primitive mouse macrophages after migration into the fetal brain...
June 23, 2017: Science
Yuan Lin, Harvind S Chahal, Wenting Wu, Hyunje G Cho, Katherine J Ransohoff, Fengju Song, Jean Y Tang, Kavita Y Sarin, Jiali Han
DNA repair plays a critical role in protecting the genome from ultraviolet radiation and maintaining the genomic integrity of cells. Genetic variants in DNA repair-related genes can influence an individual's DNA repair capacity, which may be related to the risk of developing basal cell carcinoma (BCC). We comprehensively assessed the associations of 2,965 independent single-nucleotide polymorphisms (SNPs) across 165 DNA repair pathway genes with BCC risk in a genome-wide association meta-analysis totaling 17,187 BCC cases and 287,054 controls from two data sets...
September 1, 2017: International Journal of Cancer. Journal International du Cancer
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