97 results match your criteria binds depletes

Serum microRNAs as Tool to Predict Early Response to Benralizumab in Severe Eosinophilic Asthma.

J Pers Med 2021 Jan 28;11(2). Epub 2021 Jan 28.

Department of Immunology, IIS-Fundación Jiménez Díaz, 28040 Madrid, Spain.

Severe eosinophilic asthma poses a serious health and economic problem, so new therapy approaches have been developed to control it, including biological drugs such as benralizumab, which is a monoclonal antibody that binds to IL-5 receptor alpha subunit and depletes peripheral blood eosinophils rapidly. Biomarkers that predict the response to this drug are needed so that microRNAs (miRNAs) can be useful tools. This study was performed with fifteen severe eosinophilic asthmatic patients treated with benralizumab, and serum miRNAs were evaluated before and after treatment by semi-quantitative PCR (qPCR). Read More

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January 2021

The development and hepatotoxicity of acetaminophen: reviewing over a century of progress.

Drug Metab Rev 2020 11 14;52(4):472-500. Epub 2020 Oct 14.

Department of Pharmacology and Toxicology, College of Medicine, University of Arkansas for Medical Sciences, Little Rock, AR, USA.

Acetaminophen (APAP) was first synthesized in the 1800s, and came on the market approximately 65 years ago. Since then, it has become one of the most used drugs in the world. However, it is also a major cause of acute liver failure. Read More

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November 2020

ZBTB1 Regulates Asparagine Synthesis and Leukemia Cell Response to L-Asparaginase.

Cell Metab 2020 04;31(4):852-861.e6

Laboratory of Metabolic Regulation and Genetics, The Rockefeller University, New York, NY, USA. Electronic address:

Activating transcription factor 4 (ATF4) is a master transcriptional regulator of the integrated stress response (ISR) that enables cell survival under nutrient stress. The mechanisms by which ATF4 couples metabolic stresses to specific transcriptional outputs remain unknown. Using functional genomics, we identified transcription factors that regulate the responses to distinct amino acid deprivation conditions. Read More

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A novel C2 domain binding CD33xCD3 bispecific antibody with potent T-cell redirection activity against acute myeloid leukemia.

Blood Adv 2020 03;4(5):906-919

Janssen Research & Development LLC, Spring House, PA.

CD33 is expressed in 90% of patients with acute myeloid leukemia (AML), and its extracellular portion consists of a V domain and a C2 domain. A recent study showed that a single nucleotide polymorphism (SNP), rs12459419 (C > T), results in the reduced expression of V domain-containing CD33 and limited efficacy of V domain-binding anti-CD33 antibodies. We developed JNJ-67571244, a novel human bispecific antibody capable of binding to the C2 domain of CD33 and to CD3, to induce T-cell recruitment and CD33+ tumor cell cytotoxicity independently of their SNP genotype status. Read More

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Poly-glycine-alanine exacerbates C9orf72 repeat expansion-mediated DNA damage via sequestration of phosphorylated ATM and loss of nuclear hnRNPA3.

Acta Neuropathol 2020 01 23;139(1):99-118. Epub 2019 Oct 23.

German Center for Neurodegenerative Diseases (DZNE) Munich, 81377, Munich, Germany.

Repeat expansion in C9orf72 causes amyotrophic lateral sclerosis and frontotemporal lobar degeneration. Expanded sense and antisense repeat RNA transcripts in C9orf72 are translated into five dipeptide-repeat proteins (DPRs) in an AUG-independent manner. We previously identified the heterogeneous ribonucleoprotein (hnRNP) A3 as an interactor of the sense repeat RNA that reduces its translation into DPRs. Read More

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January 2020

Rituximab in kidney disease and transplant.

Animal Model Exp Med 2019 Jun 26;2(2):76-82. Epub 2019 Mar 26.

Department of Pharmacology L. M. College of Pharmacy Ahmedabad Gujarat India.

Rituximab is a chimeric monoclonal antibody that binds to CD20 antigen of B-cells. It depletes the level of mature B-cells by various mechanisms such as mediation of antibody-dependent cellular cytotoxicity, complement-dependent cytotoxicity, and B-cell apoptosis. Rituximab is a USFDA approved drug for clinical use in non-Hodgkin's B-cell lymphoma (NHL), rheumatoid arthritis, chronic lymphocytic leukemia (CLL), granulomatosis with polyangiitis and pemphigus vulgaris. Read More

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New horizons for the treatment of severe, eosinophilic asthma: benralizumab, a novel precision biologic.

Biologics 2019 22;13:89-95. Epub 2019 May 22.

Asthma Center and Allergy Unit, Verona University Hospital, Verona, Italy.

In the last decades, the increasing evidence concerning inflammation mechanisms underlying severe eosinophilic asthma has highlighted new potential therapeutic targets and has paved the way to new selective biologic drugs. Understanding the mechanism of action and the clinical outcomes of a particular drug along with the clinical and biological characteristics of the patient population for which that drug was intended may ensure appropriate selection of patients that will respond to that drug. Under this perspective, the present review will focus on the mechanisms of action and clinical evidence of benralizumab as a treatment option for severe eosinophilic asthma, in order to provide a concise overview and a reference for clinical practice. Read More

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The Pentraxins 1975-2018: Serendipity, Diagnostics and Drugs.

Mark B Pepys

Front Immunol 2018 16;9:2382. Epub 2018 Oct 16.

Wolfson Drug Discovery Unit, Centre for Amyloidosis and Acute Phase Proteins, University College London, London, United Kingdom.

The phylogenetically ancient, pentraxin family of plasma proteins, comprises C-reactive protein (CRP) and serum amyloid P component (SAP) in humans and the homologous proteins in other species. They are composed of five, identical, non-covalently associated protomers arranged with cyclic pentameric symmetry in a disc-like configuration. Each protomer has a calcium dependent site that mediates the particular specific ligand binding responsible for all the rigorously established functional properties of these proteins. Read More

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October 2019

Spatio-temporal visualization of the distribution of acetaminophen as well as its metabolites and adducts in mouse livers by MALDI MSI.

Arch Toxicol 2018 09 23;92(9):2963-2977. Epub 2018 Jul 23.

Leibniz Research Centre for Working Environment and Human Factors at the Technical University Dortmund, Dortmund, Germany.

Acetaminophen (APAP) is one of the most intensively studied compounds that causes hepatotoxicity in the pericentral region of the liver lobules. However, spatio-temporal information on the distribution of APAP, its metabolites and GSH adducts in the liver tissue is not yet available. Here, we addressed the question, whether APAP-GSH adducts and GSH depletion show a zonated pattern and whether the distribution of APAP and its glucuronide as well as sulfate conjugates in liver lobules are zonated. Read More

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September 2018

Dynamic intercellular redistribution of HIT antigen modulates heparin-induced thrombocytopenia.

Blood 2018 08 18;132(7):727-734. Epub 2018 Jun 18.

Division of Hematology, Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, PA.

Heparin-induced thrombocytopenia (HIT) is a prothrombotic disorder initiated by antibodies to platelet factor 4 (PF4)/heparin complexes. PF4 released from platelets binds to surface glycosaminoglycans on hematopoietic and vascular cells that are heterogenous in composition and differ in affinity for PF4. PF4 binds to monocytes with higher affinity than to platelets, and depletion of monocytes exacerbates thrombocytopenia in a murine HIT model. Read More

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Pharmacokinetics and pharmacodynamics of the cytolytic anti-CD38 human monoclonal antibody TAK-079 in monkey - model assisted preparation for the first in human trial.

Pharmacol Res Perspect 2018 06 17;6(3):e00402. Epub 2018 May 17.

Takeda Pharmaceuticals International, Cambridge, Massachusetts.

We are studying the fully human, IgG1λ cytolytic monoclonal antibody TAK-079, which binds CD38. CD38 is expressed on plasma and natural killer (NK) cells constitutively and upregulated on subsets of B and T lymphocytes upon activation. TAK-079 cross-reacts with CD38 expressed by cynomolgus monkeys and depletes subsets of NK, B, and T cells. Read More

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Initial Biochemical and Functional Evaluation of Murine Calprotectin Reveals Ca(II)-Dependence and Its Ability to Chelate Multiple Nutrient Transition Metal Ions.

Biochemistry 2018 05 2;57(19):2846-2856. Epub 2018 May 2.

Department of Chemistry , Massachusetts Institute of Technology , Cambridge , Massachusetts 02139 , United States.

Calprotectin (CP) is an abundant host-defense protein that contributes to the metal-withholding innate immune response by sequestering nutrient metal ions from microbial pathogens in the extracellular space. Over the past decade, murine models of infectious disease have advanced understanding of the physiological functions of CP and its ability to compete with microbes for essential metal nutrients. Despite this extensive work, murine CP (mCP) has not been biochemically evaluated, and structural and biophysical understanding of CP is currently limited to the human orthologue. Read More

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Safety and tolerability of inebilizumab (MEDI-551), an anti-CD19 monoclonal antibody, in patients with relapsing forms of multiple sclerosis: Results from a phase 1 randomised, placebo-controlled, escalating intravenous and subcutaneous dose study.

Mult Scler 2019 02 16;25(2):235-245. Epub 2017 Nov 16.

MedImmune, Gaithersburg, MD, USA.

Background: B cells may be involved in the pathophysiology of multiple sclerosis (MS). Inebilizumab (formerly MEDI-551) binds to and depletes CD19 B cells.

Objectives: To assess safety, tolerability, pharmacokinetics, pharmacodynamics and immunogenicity of inebilizumab in adults with relapsing MS. Read More

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February 2019

Trypanosoma brucei TbIF1 inhibits the essential F1-ATPase in the infectious form of the parasite.

PLoS Negl Trop Dis 2017 04 17;11(4):e0005552. Epub 2017 Apr 17.

Biology Centre, Czech Academy of Sciences, Institute of Parasitology, Ceske Budejovice, Czech Republic.

The mitochondrial (mt) FoF1-ATP synthase of the digenetic parasite, Trypanosoma brucei, generates ATP during the insect procyclic form (PF), but becomes a perpetual consumer of ATP in the mammalian bloodstream form (BF), which lacks a canonical respiratory chain. This unconventional dependence on FoF1-ATPase is required to maintain the essential mt membrane potential (Δψm). Normally, ATP hydrolysis by this rotary molecular motor is restricted to when eukaryotic cells experience sporadic hypoxic conditions, during which this compulsory function quickly depletes the cellular ATP pool. Read More

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Inhibiting the system x/glutathione axis selectively targets cancers with mutant-p53 accumulation.

Nat Commun 2017 03 28;8:14844. Epub 2017 Mar 28.

Division of Cancer Research, Peter MacCallum Cancer Centre, Melbourne, Victoria 3000, Australia.

TP53, a critical tumour suppressor gene, is mutated in over half of all cancers resulting in mutant-p53 protein accumulation and poor patient survival. Therapeutic strategies to target mutant-p53 cancers are urgently needed. We show that accumulated mutant-p53 protein suppresses the expression of SLC7A11, a component of the cystine/glutamate antiporter, system x, through binding to the master antioxidant transcription factor NRF2. Read More

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Oridonin Triggers Chaperon-mediated Proteasomal Degradation of BCR-ABL in Leukemia.

Sci Rep 2017 01 27;7:41525. Epub 2017 Jan 27.

Key Laboratory of Gene Engineering of the Ministry of Education, State Key Laboratory for Biocontrol, Sun Yat-sen University, Guangzhou 510275, China.

Inducing degradation of oncoproteins by small molecule compounds has the potential to avoid drug resistance and therefore deserves to be exploited for new therapies. Oridonin is a natural compound with promising antitumor efficacy that can trigger the degradation of oncoproteins; however, the direct cellular targets and underlying mechanisms remain unclear. Here we report that oridonin depletes BCR-ABL through chaperon-mediated proteasomal degradation in leukemia. Read More

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January 2017

Talaromyces marneffei Mp1p Is a Virulence Factor that Binds and Sequesters a Key Proinflammatory Lipid to Dampen Host Innate Immune Response.

Cell Chem Biol 2017 Feb 19;24(2):182-194. Epub 2017 Jan 19.

State Key Laboratory of Emerging Infectious Diseases, The University of Hong Kong, Hong Kong SAR, China; Department of Microbiology, The University of Hong Kong, Hong Kong SAR, China; Research Centre of Infection and Immunology, The University of Hong Kong, Hong Kong SAR, China; Carol Yu Centre for Infection, The University of Hong Kong, Hong Kong SAR, China. Electronic address:

Talaromyces (Penicillium) marneffei is one of the leading causes of systemic mycosis in immunosuppressed or AIDS patients in Southeast Asia. How this intracellular pathogen evades the host immune defense remains unclear. We provide evidence that T. Read More

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February 2017

Relative contribution of ammonia oxidizing bacteria and other members of nitrifying activated sludge communities to micropollutant biotransformation.

Water Res 2017 Feb 22;109:217-226. Epub 2016 Nov 22.

Eawag, Swiss Federal Institute of Aquatic Science and Technology, 8600 Dübendorf, Switzerland; Institute of Biogeochemistry and Pollutant Dynamics, ETH Zürich, 8092 Zürich, Switzerland.

Improved micropollutant (MP) biotransformation during biological wastewater treatment has been associated with high ammonia oxidation activities, suggesting co-metabolic biotransformation by ammonia oxidizing bacteria as an underlying mechanism. The goal of this study was to clarify the contribution of ammonia oxidizing bacteria to increased MP degradation in nitrifying activated sludge (NAS) communities using a series of inhibition experiments. To this end, we treated a NAS community with two different ammonia oxidation inhibitors, namely octyne (OCT), a mechanistic inhibitor that covalently binds to ammonia monooxygenases, and allylthiourea (ATU), a copper chelator that depletes copper ions from the active center of ammonia monooxygenases. Read More

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February 2017

Comparative Toxicity and Metabolism of N-Acyl Homologues of Acetaminophen and Its Isomer 3'-Hydroxyacetanilide.

Chem Res Toxicol 2016 11 13;29(11):1857-1864. Epub 2016 Oct 13.

Department of Medicinal Chemistry, ‡Microscopy and Analytical Imaging Laboratory, §Mass Spectrometry Laboratory, University of Kansas , Lawrence, Kansas 66045, United States.

The hepatotoxicity of acetaminophen (APAP) is generally attributed to the formation of a reactive quinoneimine metabolite (NAPQI) that depletes glutathione and covalently binds to hepatocellular proteins. To explore the importance of the N-acyl group in APAP metabolism and toxicity, we synthesized 12 acyl side chain homologues of acetaminophen (APAP) and its 3'-regioisomer (AMAP), including the respective N-(4-pentynoyl) analogues PYPAP and PYMAP. Rat hepatocytes converted APAP, AMAP, PYPAP, and PYMAP extensively to O-glucuronide and O-sulfate conjugates in varying proportions, whereas glutathione or cysteine conjugates were observed only for APAP and PYPAP. Read More

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November 2016

Noninvasive low-level laser therapy for thrombocytopenia.

Sci Transl Med 2016 07;8(349):349ra101

Wellman Center for Photomedicine, Massachusetts General Hospital, Boston, MA 02114, USA. Department of Dermatology, Harvard Medical School, Boston, MA 02114, USA. Affiliated faculty member of the Harvard-MIT Division of Health Sciences and Technology, Cambridge, MA 02115, USA.

Thrombocytopenia is a common hematologic disorder that is managed primarily by platelet transfusions. We report here that noninvasive whole-body illumination with a special near-infrared laser cures acute thrombocytopenia triggered by γ-irradiation within 2 weeks in mice, as opposed to a 5-week recovery time required in controls. The low-level laser (LLL) also greatly accelerated platelet regeneration in the presence of anti-CD41 antibody that binds and depletes platelets, and prevented a severe drop in platelet count caused by a common chemotherapeutic drug. Read More

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Preclinical safety, pharmacokinetics, pharmacodynamics, and biodistribution studies with Ad35K++ protein: a novel rituximab cotherapeutic.

Mol Ther Methods Clin Dev 2016 30;5:16013. Epub 2016 Mar 30.

Division of Medical Genetics, University of Washington, Seattle, Washington, USA; Compliment Corp., Seattle, Washington, USA; Department of Pathology, University of Washington, Seattle, Washington, USA.

Rituximab is a mouse/human chimeric monoclonal antibody targeted toward CD20. It is efficient as first-line therapy of CD20-positive B-cell malignancies. However, a large fraction of treated patients relapse with rituximab-resistant disease. Read More

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An effector of the Irish potato famine pathogen antagonizes a host autophagy cargo receptor.

Elife 2016 Jan 14;5. Epub 2016 Jan 14.

The Sainsbury Laboratory, Norwich, United Kingdom.

Plants use autophagy to safeguard against infectious diseases. However, how plant pathogens interfere with autophagy-related processes is unknown. Here, we show that PexRD54, an effector from the Irish potato famine pathogen Phytophthora infestans, binds host autophagy protein ATG8CL to stimulate autophagosome formation. Read More

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January 2016

Enhanced Store-Operated Calcium Entry Leads to Striatal Synaptic Loss in a Huntington's Disease Mouse Model.

J Neurosci 2016 Jan;36(1):125-41

Department of Physiology, University of Texas Southwestern Medical Center, Dallas, Texas 75390, Laboratory of Molecular Neurodegeneration, St. Petersburg State Polytechnical University, St. Petersburg 195251, Russia, and

Unlabelled: In Huntington's disease (HD), mutant Huntingtin (mHtt) protein causes striatal neuron dysfunction, synaptic loss, and eventual neurodegeneration. To understand the mechanisms responsible for synaptic loss in HD, we developed a corticostriatal coculture model that features age-dependent dendritic spine loss in striatal medium spiny neurons (MSNs) from YAC128 transgenic HD mice. Age-dependent spine loss was also observed in vivo in YAC128 MSNs. Read More

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January 2016

HIV-1 Vpr Protein Induces Proteasomal Degradation of Chromatin-associated Class I HDACs to Overcome Latent Infection of Macrophages.

J Biol Chem 2016 Feb 17;291(6):2696-711. Epub 2015 Dec 17.

Cellular and Molecular Research Center (CMRC), Faculty of Medicine, Ahvaz Jundishapur University of Medical Sciences (AJUMS), Ahvaz 61357-15794, Iran, and

Mechanisms underlying HIV-1 latency remain among the most crucial questions that need to be answered to adopt strategies for purging the latent viral reservoirs. Here we show that HIV-1 accessory protein Vpr induces depletion of class I HDACs, including HDAC1, 2, 3, and 8, to overcome latency in macrophages. We found that Vpr binds and depletes chromatin-associated class I HDACs through a VprBP-dependent mechanism, with HDAC3 as the most affected class I HDAC. Read More

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February 2016

Tyrosinase-catalyzed oxidation of rhododendrol produces 2-methylchromane-6,7-dione, the putative ultimate toxic metabolite: implications for melanocyte toxicity.

Pigment Cell Melanoma Res 2014 Sep 27;27(5):744-53. Epub 2014 Jun 27.

Department of Chemistry, Fujita Health University School of Health Sciences, Toyoake, Aichi, Japan.

RS-4-(4-Hydroxyphenyl)-2-butanol (rhododendrol, RD) was used as a skin-whitening agent until it was reported to induce leukoderma in July 2013. To explore the mechanism underlying its melanocyte toxicity, we characterized the tyrosinase-catalyzed oxidation of RD using spectrophotometry and HPLC. Oxidation of RD with mushroom tyrosinase rapidly produced RD-quinone, which was quickly converted to 2-methylchromane-6,7-dione (RD-cyclic quinone) and RD-hydroxy-p-quinone through cyclization and addition of water molecule, respectively. Read More

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September 2014

Pioglitazone leads to an inactivation and disassembly of complex I of the mitochondrial respiratory chain.

BMC Biol 2013 Aug 1;11:88. Epub 2013 Aug 1.

Research Center, Laboratory of Gastroenterology and Hepatology, University Hospital 12 de Octubre, Complutense University, Madrid 28041, Spain.

Background: Thiazolidinediones are antidiabetic agents that increase insulin sensitivity but reduce glucose oxidation, state 3 respiration, and activity of complex I of the mitochondrial respiratory chain (MRC). The mechanisms of the latter effects are unclear. The aim of this study was to determine the mechanisms by which pioglitazone (PGZ), a member of the thiazolidinedione class of antidiabetic agents, decreases the activity of the MRC. Read More

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The Ets transcription factor GABP is a component of the hippo pathway essential for growth and antioxidant defense.

Cell Rep 2013 May 16;3(5):1663-77. Epub 2013 May 16.

State Key Laboratory of Stress Cell Biology, School of Life Sciences, Xiamen University, Xiang'an District, Xiamen, Fujian 361102, China.

The transcriptional coactivator Yes-associated protein (YAP) plays an important role in organ-size control and tumorigenesis. However, how Yap gene expression is regulated remains unknown. This study shows that the Ets family member GABP binds to the Yap promoter and activates YAP transcription. Read More

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12-OH-nevirapine sulfate, formed in the skin, is responsible for nevirapine-induced skin rash.

Chem Res Toxicol 2013 May 3;26(5):817-27. Epub 2013 May 3.

Leslie Dan Faculty of Pharmacy, University of Toronto , Toronto, Ontario M5S 3M2, Canada.

Nevirapine (NVP) treatment is associated with a significant incidence of skin rash in humans, and it also causes a similar immune-mediated skin rash in Brown Norway (BN) rats. We have shown that the sulfate of a major oxidative metabolite, 12-OH-NVP, covalently binds in the skin. The fact that the sulfate metabolite is responsible for covalent binding in the skin does not prove that it is responsible for the rash. Read More

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B-cell targeted therapies in systemic lupus erythematosus: successes and challenges.

BioDrugs 2013 Apr;27(2):85-95

Department of Rheumatology, Sandwell and West Birmingham Hospitals, NHS Trust, Birmingham, UK.

Systemic lupus erythematosus is a multisystem autoimmune disease characterized by the formation of autoantibodies that target a variety of self antigens. B cells are fundamental to the development of these antibodies and are a target for intervention in the disease. This review discusses four therapies that target B cells by inducing B-cell depletion, reduction in B-cell proliferation and differentiation, or modulation of B-cell function. Read More

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