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| Open AccessAn immortalized adult human erythroid line facilitates sustainable and scalable generation of functional red cells
The generation of a sustainable supply of erythroid progenitors is essential for the reliable production of anin vitroderived red blood cell clinical product. Here the authors immortalize early human erythroblasts to generate the first cell line capable of differentiation into functional adult reticulocytes.
- Kongtana Trakarnsanga
- , Rebecca E. Griffiths
- & Jan Frayne
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Article
| Open AccessAdministration of nucleoside-modified mRNA encoding broadly neutralizing antibody protects humanized mice from HIV-1 challenge
Monoclonal antibodies are highly effective therapeutics that can be delivered as proteins or encoded DNA or mRNA. Here the authors develop lipid nanoparticle-formulated nucleoside-modified mRNA encoding an HIV-1 neutralizing antibody and see sustained and protective antibody levels in treated mice.
- Norbert Pardi
- , Anthony J. Secreto
- & Drew Weissman
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Article
| Open AccessPotent single-domain antibodies that arrest respiratory syncytial virus fusion protein in its prefusion state
Neutralizing antibodies for respiratory syncytial virus (RSV) can reduce disease in hospitalized children, but current options show limited efficacy. Here, the authors isolate potent single-domain antibodies from llamas that recognize the prefusion conformation of RSV F and prevent RSV replication in mice.
- Iebe Rossey
- , Morgan S. A. Gilman
- & Xavier Saelens
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Article
| Open AccessA broadly protective therapeutic antibody against influenza B virus with two mechanisms of action
Influenza B virus (IBV) co-circulates with influenza A virus to cause annual epidemics. Here, Chaiet al. isolate a human monoclonal antibody that binds to a conserved epitope in the viral HA protein, neutralizes IBV strains in vitro, and protects mice against IBV infection.
- Ning Chai
- , Lee R. Swem
- & Man-Wah Tan
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Article
| Open AccessFunctional screening for anti-CMV biologics identifies a broadly neutralizing epitope of an essential envelope protein
Human cytomegalovirus (CMV) poses a risk for immunosuppressed patients and newborns, with limited treatment options available. Here, Gardneret al. use a high-throughput approach and identify monoclonal antibodies that bind a highly conserved domain in the viral glycoprotein gH as potent inhibitors of CMV infection.
- Thomas J. Gardner
- , Kathryn R. Stein
- & Domenico Tortorella
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Article
| Open AccessNeutralizing blood-borne polyphosphate in vivo provides safe thromboprotection
The inorganic procoagulant polymer polyphosphate participates in thrombosis via factor XII. Here the authors use recombinant probes that specifically bind or degrade circulating polyphosphate to protect mice in arterial and venous thrombosis models without an increased bleeding risk, the primary complication of all currently used anticoagulants.
- Linda Labberton
- , Ellinor Kenne
- & Thomas Renné
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Article
| Open AccessProbiotic-derived ferrichrome inhibits colon cancer progression via JNK-mediated apoptosis
Probiotics have tumour-suppressive effects in cancer cell lines and in animal models. In this study, the authors demonstrate that ferrichrome produced by Lactobacillus caseiATCC334 can suppress colon cancer growth inducing apoptosis via the JNK pathway.
- Hiroaki Konishi
- , Mikihiro Fujiya
- & Yutaka Kohgo
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| Open AccessSynthetic biology and microbioreactor platforms for programmable production of biologics at the point-of-care
Current biopharmaceutical manufacturing platforms use single biologic-producing cell lines cultured at large scales. Here the authors develop a small-scale, portable biomanufacturing platform to produce single dose IFNa2b and rHGH from a single engineered strain of P. pastoris.
- Pablo Perez-Pinera
- , Ningren Han
- & Timothy K. Lu
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Article
| Open AccessTreatment of ongoing autoimmune encephalomyelitis with activated B-cell progenitors maturing into regulatory B cells
Evidence of how functional Bregs develop in vivo has been lacking. Here the authors show that proB cells exposed in vivoto CpG differentiate into distinct Breg subsets that inhibit autoimmunity by arresting T cells in the lymph nodes via CCL19 and by producing IL-10 at the site of immunopathology.
- Sarantis Korniotis
- , Christophe Gras
- & Flora Zavala
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Article
| Open AccessMicrofluidic single-cell transcriptional analysis rationally identifies novel surface marker profiles to enhance cell-based therapies
Unrecognized progenitor cell perturbations underlying a disease state may limit the efficacy of cell therapies. Here, the authors use high-throughput, single-cell transcriptional analysis to identify disease-specific cellular alterations and prospectively isolate restorative cell subpopulations.
- Robert C. Rennert
- , Michael Januszyk
- & Geoffrey C. Gurtner
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Article
| Open AccessPolyMetformin combines carrier and anticancer activities for in vivo siRNA delivery
The anti-diabetic drug Metformin also possesses anti-tumour activity. Here, the authors synthesize polymeric Metformin-based nanoparticles that still exert intrinsic biological activity through AMPK and mTOR regulation and can systematically deliver VEGF siRNA, significantly reducing lung cancer growth in mice.
- Yi Zhao
- , Wei Wang
- & Leaf Huang
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Article
| Open AccessA bispecific antibody targeting sclerostin and DKK-1 promotes bone mass accrual and fracture repair
Antibodies that block the Wnt inhibitors sclerostin and DKK- 1 enhance bone formation and fracture repair. Here the authors show these monospecific antibodies induce compensatory mechanisms that limit efficacy, and have designed a sclerostin/DKK-1 bispecific antibody that promotes superior fracture repair in rodents and bone formation in primates.
- Monica Florio
- , Kannan Gunasekaran
- & Michael S. Ominsky
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Article
| Open AccessElimination of HIV-1-infected cells by broadly neutralizing antibodies
Broadly neutralizing antibodies (bNAbs) are promising as potential therapies targeting HIV-1 but their overall antiviral activity remains to be fully elucidated. Here the authors evaluate the ability of a panel of bNAbs to trigger antibody-dependent cellular cytotoxicity and identify the most effective antibody combinations.
- Timothée Bruel
- , Florence Guivel-Benhassine
- & Olivier Schwartz
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Article
| Open AccessRationally engineered Troponin C modulates in vivo cardiac function and performance in health and disease
Heart contraction, which is decreased in disease, is determined by Ca2+binding to troponin C. Here, the authors combine a protein engineering approach with gene therapy to modulate heart contractility in mice with the use of rationally designed Troponin C variants, suggesting a new therapy for diseased hearts.
- Vikram Shettigar
- , Bo Zhang
- & Jonathan P. Davis
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Article
| Open AccessWhole-genome mutational burden analysis of three pluripotency induction methods
It is feared that reprogramming may introduce DNA mutations. Here Bhutani et al. take three different reprogramming methods and using comparative whole genome analyses do identify nucleotide variations that are different in reprogrammed cells from the original fibroblasts, but none convey oncogenic potential.
- Kunal Bhutani
- , Kristopher L. Nazor
- & Jeanne F. Loring
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| Open AccessPrecision multidimensional assay for high-throughput microRNA drug discovery
Progress in drug discovery can be hampered by a limited exploration of chemical space and the difficulty in assessing the full range of drug candidates’ effects on living cells. Here the authors describe a cell-based assay to distinguish between off-target and specific effects of candidate compounds targeting micro RNAs.
- Benjamin Haefliger
- , Laura Prochazka
- & Yaakov Benenson
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Article
| Open AccessTherapeutically engineered induced neural stem cells are tumour-homing and inhibit progression of glioblastoma
Neural stem cells have a tropism for glioblastoma. Here the authors employ fibroblasts directly reprogrammed into induced neural stem cells and loaded with cytotoxic molecules to migrate to xenotransplanted brain tumours in mice, achieving tumour shrinkage and prolonged survival.
- Juli R. Bagó
- , Adolfo Alfonso-Pecchio
- & Shawn D. Hingtgen
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| Open AccessAutonomous beating rate adaptation in human stem cell-derived cardiomyocytes
The use of stem cell-derived cardiomyocytes for heart repair is hampered by their immature structural and contractile properties that may cause arrhythmia. Here, Eng et al.show that electrical conditioning of human cardiomyocytes in 3D culture can enhance connectivity and provide resistance to arrhythmia.
- George Eng
- , Benjamin W. Lee
- & Gordana Vunjak-Novakovic
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| Open AccessMulti-reporter selection for the design of active and more specific zinc-finger nucleases for genome editing
Zinc finger nucleases have an established role in genome editing. Here, the authors report a strategy for identifying zinc finger nucleases that discriminate between desired targets and provide genome-wide specificity.
- Benjamin L. Oakes
- , Danny F. Xia
- & Marcus B. Noyes
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Article
| Open AccessSepsis induces long-term metabolic and mitochondrial muscle stem cell dysfunction amenable by mesenchymal stem cell therapy
Sepsis patients often develop muscle atrophy that can last for years. Here the authors show in a mouse model that sepsis causes long-term impairment of the satellite cells, affecting mitochondrial function and energy metabolism, and that injection of mesenchymal stem cells restores satellite cell metabolism and muscle regeneration.
- P. Rocheteau
- , L. Chatre
- & F. Chrétien
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Article
| Open AccessENPP1-Fc prevents mortality and vascular calcifications in rodent model of generalized arterial calcification of infancy
Generalized arterial calcification of infancy (GACI) is a terminal disease caused by the ENPP1 enzyme deficiency. Here, Albrigh et al. show that ENPP1 enzyme replacement therapy prevents the ectopic calcifications and mortality in mice with GACI, suggesting a novel treatment for vascular calcification in humans.
- Ronald A. Albright
- , Paul Stabach
- & Demetrios T. Braddock
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Article
| Open AccessRescue of neonatal cardiac dysfunction in mice by administration of cardiac progenitor cells in utero
The protein Speg is expressed in the developing mouse heart, where its absence leads to neonatal cardiac disease. Here the authors trace the cardiomyopathy of Speg KO mice back to defects in cardiac progenitor cells (CPCs) and rescue it with injections of wild type CPCs into the foetal heart.
- Xiaoli Liu
- , Sean R. R. Hall
- & Mark A. Perrella
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Article
| Open AccessResident c-kit+ cells in the heart are not cardiac stem cells
The issue whether the cell surface protein c-kit identifies resident cardiac stem cells (CSC) is controversial. By using novel reporter mouse models, Sultana et al. show that c-kit+cells represent a subpopulation of endothelial cells in the developing and adult heart and do not exhibit CSC traits in health or disease.
- Nishat Sultana
- , Lu Zhang
- & Chen-Leng Cai
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Article
| Open AccessDirecting cell therapy to anatomic target sites in vivo with magnetic resonance targeting
Cell therapy requires the targeting of cells to specific sites in the body. Here Muthana et al.use a standard MRI scanner to direct oncolytic macrophages, labelled with magnetic nanoparticles, to primary and metastatic tumour sites in mice, and demonstrate that this leads to reduced tumour growth.
- Munitta Muthana
- , Aneurin J. Kennerley
- & Claire Lewis
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Nanoparticles that deliver triplex-forming peptide nucleic acid molecules correct F508del CFTR in airway epithelium
Cystic fibrosis is a lethal genetic disorder commonly caused by the F508del mutation which is not amenable to gene therapy. Here, the authors use triplex-forming PNA molecules and donor DNA in biodegradable polymer nanoparticles to correct F508del and achieve clinically relevant levels of gene editing.
- Nicole Ali McNeer
- , Kavitha Anandalingam
- & Marie E. Egan
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Article
| Open AccessA plug-and-play approach to antibody-based therapeutics via a chemoselective dual click strategy
Antibody–drug conjugates are a class of therapeutic combining the directing ability of antibodies with the cell-killing ability of cytotoxic drugs. Here the authors describe an approach based on click chemistry that enables the rapid assembly of dual-modified antibodies with potential for new therapeutic modalities.
- Antoine Maruani
- , Mark E.B. Smith
- & Stephen Caddick
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Immunotoxin targeting glypican-3 regresses liver cancer via dual inhibition of Wnt signalling and protein synthesis
Tumour-targeted antibodies can kill cancer cells by blocking pro-survival signalling or by delivering a toxin. Here the authors show that glypican-3 antibody fused to a bacterial toxin suppresses tumour growth more efficiently if designed to block Wnt signalling downstream of glypican-3.
- Wei Gao
- , Zhewei Tang
- & Mitchell Ho
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Article
| Open AccessStereochemical bias introduced during RNA synthesis modulates the activity of phosphorothioate siRNAs
Therapeutic oligonucleotides can be made more stable by substituting their achiral phosphodiester groups for chiral phosphorothioate linkages. Here, the authors present a synthesis of phosphorothioated RNAs, where the activator controls strand stereochemistry, and also the activity of assembled siRNAs.
- Hartmut Jahns
- , Martina Roos
- & Jonathan Hall
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Article
| Open AccessGene therapy restores vision in rd1 mice after removal of a confounding mutation in Gpr179
The rd1 mouse is the most widely used model to study retinal degeneration. Here, the authors identify a wide-spread mutation in these mice that may explain the failure of previous gene therapeutic approaches and show that long-lasting restoration of vision is possible in rd1 mice without this mutation.
- Koji M. Nishiguchi
- , Livia S. Carvalho
- & Robin R. Ali
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PD-L1hi B cells are critical regulators of humoral immunity
Follicular helper T cells promote antibody production by B cells, and regulatory B cells, in turn, can restrain T cell activation. Here, Khan et al. show that PD-L1 plays a critical role in regulatory B cell function, curbing excessive immune responses by engaging the PD-1 receptor on follicular helper T cells.
- Adnan R. Khan
- , Emily Hams
- & Padraic G. Fallon
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Article
| Open AccessCell type-specific delivery of short interfering RNAs by dye-functionalised theranostic nanoparticles
A potential drug should specifically interact with its intended target in order to limit unwanted side effects. Here, the authors fabricate a biodegradable polymer nanoparticle with a fluorescent hepatic uptake transporter ligand to achieve targeted in vivosiRNA delivery and imaging of delivery.
- Adrian T. Press
- , Anja Traeger
- & Michael Bauer
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Mybpc3 gene therapy for neonatal cardiomyopathy enables long-term disease prevention in mice
Hereditary hypertrophic cardiomyopathy (HCM) is caused by mutations in cardiomyocyte genes, such as MYBPC3. Here, the authors use virus-mediated gene therapy to correct Mycbpc3mutations in 1-day-old mice and, by administering just a single dose, prevent development of HCM over a period of 34 weeks.
- Giulia Mearini
- , Doreen Stimpel
- & Lucie Carrier
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An authentic imaging probe to track cell fate from beginning to end
The availability of tracers to track the health of cells over long periods of time will be of value to optimize cell-based therapy. Here, Lee et al.design a nanoparticle that fluoresces red in living cells, but fluoresces green when cells begin to die from apoptosis or necrosis.
- Seung Koo Lee
- , Luke J. Mortensen
- & Ching-Hsuan Tung
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Treatment of acute lung injury by targeting MG53-mediated cell membrane repair
MG53 acts as a membrane repair protein in striatal muscle. Here the authors report that MG53 is also expressed in the lung, where it exerts a similar repair function in the context of pulmonary epithelial damage, and show that administration of recombinant MG53 ameliorates lung injury in mice.
- Yanlin Jia
- , Ken Chen
- & Jianjie Ma
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Article |
FOXO1 inhibition yields functional insulin-producing cells in human gut organoid cultures
The transcription factor FOXO1 has been shown to control the differentiation of enteroendocrine cells in mice. Here the authors extend these findings to humans by showing that FOXO1-expressing cells also exist in the human gut, and that inhibition of FOXO1 generates insulin-secreting cells in human gut organoid cultures.
- Ryotaro Bouchi
- , Kylie S. Foo
- & Domenico Accili
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Article |
Nanoparticle-formulated siRNA targeting integrins inhibits hepatocellular carcinoma progression in mice
Integrin proteins regulate important cellular processes such as proliferation and differentiation. Here the authors show that siRNA-mediated knockdown of two integrin subunits slows down progression of hepatocellular carcinoma in mice by reducing activation of the METoncogene.
- Roman L. Bogorad
- , Hao Yin
- & Victor Koteliansky
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Article |
Protein grafting of p53TAD onto a leucine zipper scaffold generates a potent HDM dual inhibitor
The protein levels of the tumour suppressor p53 can be negatively regulated by HDM2, which is an attractive target for cancer therapy. In this study, Lee et al. graft the transactivation domain of p53 onto a scaffold protein and show that this binds to HDM2 and inhibits cancer cell growth in vitro.
- Jung-Hoon Lee
- , Eunji Kang
- & Jae Il Lee
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Article |
Two potential therapeutic antibodies bind to a peptide segment of membrane-bound IgE in different conformations
Two antibodies targeting the CεmX domain of membrane-bound IgE on human B lymphocytes are being developed to treat allergy. Here, the authors map the antigenic epitopes of the two antibodies and show that they bind to different conformations of the same peptide region.
- Hsing-Mao Chu
- , Jon Wright
- & Carmay Lim
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Article
| Open AccesshESC-derived Olig2+ progenitors generate a subtype of astroglia with protective effects against ischaemic brain injury
Astroglia are heterogeneous in phenotype and not all astrocytes are equivalent in their ability to repair injured brain. Here, the authors show that two defined subtypes of astroglia generated from hESC-derived Olig2-positive versus Olig2-negative neural progenitors, exhibit distinct properties and neuroprotective effects.
- Peng Jiang
- , Chen Chen
- & Wenbin Deng
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Article |
An influenza virus-inspired polymer system for the timed release of siRNA
Small interfering RNA is degraded by plasma and can’t cross the cell membrane due to its negative charge. Here, the authors present an influenza inspired polymer carrier, capable of local RNA delivery, which degrades to a non-toxic by-product, and is thus suitable for multiple doses.
- Nghia P Truong
- , Wenyi Gu
- & Michael J Monteiro
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Article |
An ex vivo gene therapy approach to treat muscular dystrophy using inducible pluripotent stem cells
Patient-specific induced pluripotent stem (iPS) cells hold great potential for regenerative cell therapies. Here Filareto et al. genetically correct iPS cells from mice with muscular dystrophy and use these cells to treat the same animals, providing a proof-of-principle for autologous iPS cell therapy.
- Antonio Filareto
- , Sarah Parker
- & Rita C. R. Perlingeiro
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Article |
Production of α-L-iduronidase in maize for the potential treatment of a human lysosomal storage disease
The lysosomal storage disease mucopolysaccharidosis I is treated with recombinant α-L-iduronidase but production of the enzyme is expensive. In this study, α-L-iduronidase is compartmentalized within the endosperm of maize via a unique mRNA strategy yielding the active, correctly glycosylated protein.
- Xu He
- , Thomas Haselhorst
- & Allison R. Kermode
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Article
| Open AccessTargeted suppression of claudin-5 decreases cerebral oedema and improves cognitive outcome following traumatic brain injury
Claudin-5 is a component of tight junctions and has important roles in mediating the permeability of the blood-brain barrier. Campbell and co-workers administer short interfering RNA against claudin-5 in a model of brain injury, finding that it enhances water movement from the brain to the blood and alleviates swelling.
- Matthew Campbell
- , Finnian Hanrahan
- & Peter Humphries
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Article
| Open AccessMuscle-derived stem/progenitor cell dysfunction limits healthspan and lifespan in a murine progeria model
The function of adult stem cells is diminished with age but the role this dysfunction plays in the aging process is unknown. Here, the injection of muscle-derived stem/progenitor cells from young mice rescues symptoms in progeroid mice and is shown to regenerate tissues independent of engraftment.
- Mitra Lavasani
- , Andria R. Robinson
- & Johnny Huard
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Article |
A role for T-bet-mediated tumour immune surveillance in anti-IL-17A treatment of lung cancer
The tumour microenvironment is often found to be immunosuppressive. Reppert and colleagues show that human and murine lung tumours harbour IL-17A-producing T cells, and that blocking IL-17A increases survival in mice, suggesting that anti-IL-17A therapy may be useful in treating lung cancer.
- S. Reppert
- , I. Boross
- & S. Finotto
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Article
| Open AccessCompetition for FcRn-mediated transport gives rise to short half-life of human IgG3 and offers therapeutic potential
The half-life of IgG is regulated by binding to the neonatal Fc receptor and, in the case of IgG3, is reduced compared to other IgG proteins. In this study, a mutation in IgG3 is shown to reduce binding to the neonatal Fc receptor, which can be competitively blocked by IgG1.
- Nigel M. Stapleton
- , Jan Terje Andersen
- & Gestur Vidarsson
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