12 results on '"Joanne J. Bronson"'
Search Results
2. Enhancing the Visibility of Women in the ACS Division of Medicinal Chemistry (ACS MEDI).
- Author
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Aldrich J, Allen S, Araujo E, Bronson J, Bryant-Friedrich A, Cyr SK, DiMauro EF, Dzierba C, Garner AL, Georg GI, Goodwin NC, Haranahalli K, Huang R, Leftheris K, May-Dracka TL, Olson ME, and Blanco MJ
- Abstract
On the occasion of the 2023 International Women's Day on March 8, 2023, we want to celebrate and highlight the contributions of many women volunteers in the American Chemical Society Division of Medicinal Chemistry (ACS MEDI)., (Published 2023 by American Chemical Society.)
- Published
- 2023
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3. Discovery of non-zwitterionic aryl sulfonamides as Na v 1.7 inhibitors with efficacy in preclinical behavioral models and translational measures of nociceptive neuron activation.
- Author
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Wu YJ, Guernon J, McClure A, Luo G, Rajamani R, Ng A, Easton A, Newton A, Bourin C, Parker D, Mosure K, Barnaby O, Soars MG, Knox RJ, Matchett M, Pieschl R, Herrington J, Chen P, Sivarao DV, Bristow LJ, Meanwell NA, Bronson J, Olson R, Thompson LA, and Dzierba C
- Subjects
- Administration, Oral, Animals, Chronic Pain chemically induced, Chronic Pain drug therapy, Disease Models, Animal, Dose-Response Relationship, Drug, Freund's Adjuvant, HEK293 Cells, Humans, Inflammation chemically induced, Inflammation drug therapy, Male, Mice, Molecular Structure, Neurons metabolism, Structure-Activity Relationship, Sulfonamides administration & dosage, Sulfonamides chemistry, Drug Discovery, Models, Biological, NAV1.7 Voltage-Gated Sodium Channel metabolism, Neurons drug effects, Nociception drug effects, Sulfonamides pharmacology
- Abstract
Since zwitterionic benzenesulfonamide Na
v 1.7 inhibitors suffer from poor membrane permeability, we sought to eliminate this characteristic by replacing the basic moiety with non-basic bicyclic acetals and monocyclic ethers. These efforts led to the discovery of the non-zwitterionic aryl sulfonamide 49 as a selective Nav 1.7 inhibitor with improved membrane permeability. Despite its moderate cellular activity, 49 exhibited robust efficacy in mouse models of neuropathic and inflammatory pain and modulated translational electromyogram measures associated with activation of nociceptive neurons., (Copyright © 2017 Elsevier Ltd. All rights reserved.)- Published
- 2017
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4. [ 3 H]BMT-046091 a potent and selective radioligand to determine AAK1 distribution and target engagement.
- Author
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Louis JV, Lu Y, Pieschl R, Tian Y, Hong Y, Dandapani K, Naidu S, Vikramadithyan RK, Dzierba C, Sarvasiddhi SK, Nara SJ, Bronson J, Macor JE, Albright C, Kostich W, and Li YW
- Subjects
- Amines pharmacokinetics, Animals, Autoradiography, Brain diagnostic imaging, Brain metabolism, Cyclohexanecarboxylic Acids pharmacokinetics, Disease Models, Animal, Dose-Response Relationship, Drug, Enzyme Inhibitors chemistry, Functional Laterality, Gabapentin, Haplorhini, Hyperalgesia etiology, Inhibitory Concentration 50, Male, Mice, Mice, Knockout, Naphthyridines chemistry, Naphthyridines pharmacokinetics, Neuralgia etiology, Neuralgia metabolism, Protein Binding drug effects, Protein Binding genetics, Protein Serine-Threonine Kinases genetics, Radioligand Assay, Rats, Tritium pharmacokinetics, gamma-Aminobutyric Acid pharmacokinetics, Brain drug effects, Enzyme Inhibitors pharmacokinetics, Protein Serine-Threonine Kinases metabolism, Spinal Cord Injuries complications
- Abstract
Adaptor-associated kinase 1 (AAK1), a member of the Ark1/Prk1 family of serine/threonine kinases, plays a role in modulating clatherin coated endocytosis of specific surface receptors. We have demonstrated that AAK1 inhibitors are efficacious in rodent models of neuropathic pain (Kostich et al., 2016). Here we have characterized the binding properties and distribution pattern of the tritiated AAK1 radioligand, [
3 H]BMT-046091, in rodents and cynomolgus monkeys, and used the radioligand to measure the brain target occupancy following systemic administration of AAK1 inhibitors. We have found that [3 H]BMT-046091 is potent and selective AAK1 inhibitor. It inhibits AAK1 phosphorylation of a peptide derived from a physiologic substrate, the μ2 subunit of the adaptor protein complex, with an IC50 value of 2.8 nM, and is inactive at >5 μM in a panel of functional or binding assays for receptors, transporters and enzymes. [3 H]BMT-046091 binding in the brain is absent in the AAK1 knockout mouse, and is displaceable with a high concentration of AAK1 inhibitors in wild type mice. Specific [3 H]BMT-046091 binding is widespread in the brain and spinal cord with the highest density in the cortex, hippocampus, amygdala, striatum and thalamus. In the spinal cord, [3 H]BMT-046091 binding appears enriched in the dorsal horn superficial layers. Oral administration of LP-935509, an AAK1 inhibitor, results in a dose-dependent occupation of AAK1 binding sites in the brain and spinal cord. The increase in AAK1 binding site occupancy by LP-935509 correlates with the decrease in antinociceptive responses in the rat chronic constriction injury model of neuropathic pain., (Copyright © 2017 Elsevier Ltd. All rights reserved.)- Published
- 2017
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5. Inhibition of AAK1 Kinase as a Novel Therapeutic Approach to Treat Neuropathic Pain.
- Author
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Kostich W, Hamman BD, Li YW, Naidu S, Dandapani K, Feng J, Easton A, Bourin C, Baker K, Allen J, Savelieva K, Louis JV, Dokania M, Elavazhagan S, Vattikundala P, Sharma V, Das ML, Shankar G, Kumar A, Holenarsipur VK, Gulianello M, Molski T, Brown JM, Lewis M, Huang Y, Lu Y, Pieschl R, O'Malley K, Lippy J, Nouraldeen A, Lanthorn TH, Ye G, Wilson A, Balakrishnan A, Denton R, Grace JE, Lentz KA, Santone KS, Bi Y, Main A, Swaffield J, Carson K, Mandlekar S, Vikramadithyan RK, Nara SJ, Dzierba C, Bronson J, Macor JE, Zaczek R, Westphal R, Kiss L, Bristow L, Conway CM, Zambrowicz B, and Albright CF
- Subjects
- Animals, Electrophysiological Phenomena drug effects, Gene Knockout Techniques, HEK293 Cells, Humans, Male, Mice, Neuralgia metabolism, Neuralgia physiopathology, Nociception drug effects, Phenotype, Protein Kinase Inhibitors therapeutic use, Protein Serine-Threonine Kinases deficiency, Protein Serine-Threonine Kinases genetics, Rats, Spinal Cord drug effects, Spinal Cord enzymology, Spinal Cord physiopathology, Neuralgia drug therapy, Protein Kinase Inhibitors pharmacology, Protein Serine-Threonine Kinases antagonists & inhibitors
- Abstract
To identify novel targets for neuropathic pain, 3097 mouse knockout lines were tested in acute and persistent pain behavior assays. One of the lines from this screen, which contained a null allele of the adapter protein-2 associated kinase 1 (AAK1) gene, had a normal response in acute pain assays (hot plate, phase I formalin), but a markedly reduced response to persistent pain in phase II formalin. AAK1 knockout mice also failed to develop tactile allodynia following the Chung procedure of spinal nerve ligation (SNL). Based on these findings, potent, small-molecule inhibitors of AAK1 were identified. Studies in mice showed that one such inhibitor, LP-935509, caused a reduced pain response in phase II formalin and reversed fully established pain behavior following the SNL procedure. Further studies showed that the inhibitor also reduced evoked pain responses in the rat chronic constriction injury (CCI) model and the rat streptozotocin model of diabetic peripheral neuropathy. Using a nonbrain-penetrant AAK1 inhibitor and local administration of an AAK1 inhibitor, the relevant pool of AAK1 for antineuropathic action was found to be in the spinal cord. Consistent with these results, AAK1 inhibitors dose-dependently reduced the increased spontaneous neural activity in the spinal cord caused by CCI and blocked the development of windup induced by repeated electrical stimulation of the paw. The mechanism of AAK1 antinociception was further investigated with inhibitors of α2 adrenergic and opioid receptors. These studies showed that α2 adrenergic receptor inhibitors, but not opioid receptor inhibitors, not only prevented AAK1 inhibitor antineuropathic action in behavioral assays, but also blocked the AAK1 inhibitor-induced reduction in spinal neural activity in the rat CCI model. Hence, AAK1 inhibitors are a novel therapeutic approach to neuropathic pain with activity in animal models that is mechanistically linked (behaviorally and electrophysiologically) to α2 adrenergic signaling, a pathway known to be antinociceptive in humans., (Copyright © 2016 The Author(s).)
- Published
- 2016
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6. Discovery of D1 Dopamine Receptor Positive Allosteric Modulators: Characterization of Pharmacology and Identification of Residues that Regulate Species Selectivity.
- Author
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Lewis MA, Hunihan L, Watson J, Gentles RG, Hu S, Huang Y, Bronson J, Macor JE, Beno BR, Ferrante M, Hendricson A, Knox RJ, Molski TF, Kong Y, Cvijic ME, Rockwell KL, Weed MR, Cacace AM, Westphal RS, Alt A, and Brown JM
- Subjects
- Animals, CHO Cells, Cell Line, Cells, Cultured, Cricetulus, HEK293 Cells, Humans, Mice, Rats, Schizophrenia drug therapy, Allosteric Regulation drug effects, Receptors, Dopamine D1 agonists, Receptors, Dopamine D2 agonists
- Abstract
The present studies represent the first published report of a dopamine D1 positive allosteric modulator (PAM). D1 receptors have been proposed as a therapeutic target for the treatment of cognitive deficits associated with schizophrenia. However, the clinical utility of orthosteric agonist compounds is limited by cardiovascular side effects, poor pharmacokinetics, lack of D1 selectivity, and an inverted dose response. A number of these challenges may be overcome by utilization of a selective D1 PAM. The current studies describe two chemically distinct D1 PAMs: Compound A [1-((rel-1S,3R,6R)-6-(benzo[d][1,3]dioxol-5-yl)bicyclo[4.1.0]heptan-3-yl)-4-(2-bromo-5-chlorobenzyl)piperazine] and Compound B [rel-(9R,10R,12S)-N-(2,6-dichloro-3-methylphenyl)-12-methyl-9,10-dihydro-9,10-ethanoanthracene-12-carboxamide]. Compound A shows pure PAM activity, with an EC50 of 230 nM and agonist activity at the D2 receptor in D2-expressing human embryonic kidney cells. Compound B shows superior potency (EC50 of 43 nM) and selectivity for D1 versus D2 dopamine receptors. Unlike Compound A, Compound B is selective for human and nonhuman primate D1 receptors, but lacks activity at the rodent (rat and mouse) D1 receptors. Using molecular biology techniques, a single amino acid was identified at position 130, which mediates the species selectivity of Compound B. These data represent the first described D1-selective PAMs and define critical amino acids that regulate species selectivity., (Copyright © 2015 by The American Society for Pharmacology and Experimental Therapeutics.)
- Published
- 2015
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7. In vitro Characterization of a small molecule inhibitor of the alanine serine cysteine transporter -1 (SLC7A10).
- Author
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Brown JM, Hunihan L, Prack MM, Harden DG, Bronson J, Dzierba CD, Gentles RG, Hendricson A, Krause R, Macor JE, and Westphal RS
- Subjects
- Amino Acids metabolism, Animals, Cell Line, Cerebral Cortex cytology, Cerebral Cortex drug effects, Cerebral Cortex metabolism, Glycine metabolism, Histidine chemical synthesis, Histidine pharmacology, Humans, Rats, Rats, Sprague-Dawley, Serine metabolism, Small Molecule Libraries, Synaptosomes metabolism, Amino Acid Transport System y+ antagonists & inhibitors, Excitatory Amino Acid Agonists pharmacology, Histidine analogs & derivatives, Indoles chemical synthesis, Indoles pharmacology, Receptors, N-Methyl-D-Aspartate agonists
- Abstract
NMDA receptor hypofunction is hypothesized to contribute to cognitive deficits associated with schizophrenia. Since direct activation of NMDA receptors is associated with serious adverse effects, modulation of the NMDA co-agonists, glycine or D-serine, represents a viable alternative therapeutic approach. Indeed, clinical trials with glycine and D-serine have shown positive results, although concerns over toxicity related to the high-doses required for efficacy remain. Synaptic concentrations of D-serine and glycine are regulated by the amino acid transporter alanine serine cysteine transporter-1 (asc-1). Inhibition of asc-1 would increase synaptic D-serine and possibly glycine, eliminating the need for high-dose systemic D-serine or glycine treatment. In this manuscript, we characterize Compound 1 (BMS-466442), the first known small molecule inhibitor of asc-1. Compound 1 selectively inhibited asc-1 mediated D-serine uptake with nanomolar potency in multiple cellular systems. Moreover, Compound 1 inhibited asc-1 but was not a competitive substrate for this transporter. Compound 1 is the first reported selective inhibitor of the asc-1 transporter and may provide a new path for the development of asc-1 inhibitors for the treatment of schizophrenia., (© 2013 International Society for Neurochemistry.)
- Published
- 2014
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8. Discovery of a cyclopentylamine as an orally active dual NK1 receptor antagonist-serotonin reuptake transporter inhibitor.
- Author
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Wu YJ, He H, Gao Q, Wu D, Bertekap R, Westphal RS, Lelas S, Newton A, Wallace T, Taber M, Davis C, Macor JE, and Bronson J
- Subjects
- Administration, Oral, Animals, Crystallography, X-Ray, Cyclopentanes chemical synthesis, Cyclopentanes pharmacology, Drug Evaluation, Preclinical, Gerbillinae, Humans, Molecular Conformation, Motor Activity drug effects, Neurokinin-1 Receptor Antagonists metabolism, Neurokinin-1 Receptor Antagonists pharmacology, Protein Binding, Receptors, Neurokinin-1 metabolism, Serotonin Plasma Membrane Transport Proteins metabolism, Selective Serotonin Reuptake Inhibitors chemical synthesis, Selective Serotonin Reuptake Inhibitors pharmacology, Cyclopentanes chemistry, Neurokinin-1 Receptor Antagonists chemistry, Receptors, Neurokinin-1 chemistry, Serotonin Plasma Membrane Transport Proteins chemistry, Selective Serotonin Reuptake Inhibitors chemistry
- Abstract
Cyclopentylamine 4 was identified as a potent dual NK1R antagonist-SERT inhibitor. This compound demonstrated significant oral activity in the gerbil forced swimming test, suggesting that dual NK1R antagonists-SERT inhibitors may be useful in treating depression disorders., (Copyright © 2014 Elsevier Ltd. All rights reserved.)
- Published
- 2014
- Full Text
- View/download PDF
9. Discovery of disubstituted piperidines and homopiperidines as potent dual NK1 receptor antagonists-serotonin reuptake transporter inhibitors for the treatment of depression.
- Author
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Wu YJ, He H, Bertekap R, Westphal R, Lelas S, Newton A, Wallace T, Taber M, Davis C, Macor JE, and Bronson J
- Subjects
- Antidepressive Agents chemistry, Antidepressive Agents pharmacology, Astrocytes cytology, Astrocytes drug effects, Cell Line, HEK293 Cells, Humans, Piperidines chemical synthesis, Receptors, Neurokinin-1 metabolism, Serotonin Plasma Membrane Transport Proteins biosynthesis, Serotonin Plasma Membrane Transport Proteins genetics, Selective Serotonin Reuptake Inhibitors chemical synthesis, Structure-Activity Relationship, Neurokinin-1 Receptor Antagonists chemistry, Neurokinin-1 Receptor Antagonists pharmacology, Piperidines chemistry, Piperidines pharmacology, Selective Serotonin Reuptake Inhibitors chemistry, Selective Serotonin Reuptake Inhibitors pharmacology
- Abstract
This report describes the synthesis, structure-activity relationships and activity of piperidine, homopiperidine, and azocane derivatives combining NK1 receptor (NK1R) antagonism and serotonin reuptake transporter (SERT) inhibition. Our studies culminated in the discovery of piperidine 2 and homopiperidine 8 as potent dual NK1R antagonists-SERT inhibitors. Compound 2 demonstrated significant activity in the gerbil forced swimming test, suggesting that dual NK1R antagonists-SERT inhibitors may be useful in treating depression disorders., (Copyright © 2013 Elsevier Ltd. All rights reserved.)
- Published
- 2013
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10. Pharmacodynamics of selective inhibition of γ-secretase by avagacestat.
- Author
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Albright CF, Dockens RC, Meredith JE Jr, Olson RE, Slemmon R, Lentz KA, Wang JS, Denton RR, Pilcher G, Rhyne PW, Raybon JJ, Barten DM, Burton C, Toyn JH, Sankaranarayanan S, Polson C, Guss V, White R, Simutis F, Sanderson T, Gillman KW, Starrett JE Jr, Bronson J, Sverdlov O, Huang SP, Castaneda L, Feldman H, Coric V, Zaczek R, Macor JE, Houston J, Berman RM, and Tong G
- Subjects
- Adolescent, Adult, Amyloid beta-Peptides metabolism, Amyloid beta-Protein Precursor metabolism, Animals, Cells, Cultured, Dogs, Female, Humans, Male, Middle Aged, Rats, Rats, Sprague-Dawley, Receptors, Notch metabolism, Signal Transduction drug effects, Young Adult, Amyloid Precursor Protein Secretases antagonists & inhibitors, Amyloid beta-Protein Precursor antagonists & inhibitors, Oxadiazoles pharmacology, Sulfonamides pharmacology
- Abstract
A hallmark of Alzheimer's disease (AD) pathology is the accumulation of brain amyloid β-peptide (Aβ), generated by γ-secretase-mediated cleavage of the amyloid precursor protein (APP). Therefore, γ-secretase inhibitors (GSIs) may lower brain Aβ and offer a potential new approach to treat AD. As γ-secretase also cleaves Notch proteins, GSIs can have undesirable effects due to interference with Notch signaling. Avagacestat (BMS-708163) is a GSI developed for selective inhibition of APP over Notch cleavage. Avagacestat inhibition of APP and Notch cleavage was evaluated in cell culture by measuring levels of Aβ and human Notch proteins. In rats, dogs, and humans, selectivity was evaluated by measuring plasma blood concentrations in relation to effects on cerebrospinal fluid (CSF) Aβ levels and Notch-related toxicities. Measurements of Notch-related toxicity included goblet cell metaplasia in the gut, marginal-zone depletion in the spleen, reductions in B cells, and changes in expression of the Notch-regulated hairy and enhancer of split homolog-1 from blood cells. In rats and dogs, acute administration of avagacestat robustly reduced CSF Aβ40 and Aβ42 levels similarly. Chronic administration in rats and dogs, and 28-day, single- and multiple-ascending-dose administration in healthy human subjects caused similar exposure-dependent reductions in CSF Aβ40. Consistent with the 137-fold selectivity measured in cell culture, we identified doses of avagacestat that reduce CSF Aβ levels without causing Notch-related toxicities. Our results demonstrate the selectivity of avagacestat for APP over Notch cleavage, supporting further evaluation of avagacestat for AD therapy.
- Published
- 2013
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11. Small molecule receptor protein tyrosine phosphatase γ (RPTPγ) ligands that inhibit phosphatase activity via perturbation of the tryptophan-proline-aspartate (WPD) loop.
- Author
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Sheriff S, Beno BR, Zhai W, Kostich WA, McDonnell PA, Kish K, Goldfarb V, Gao M, Kiefer SE, Yanchunas J, Huang Y, Shi S, Zhu S, Dzierba C, Bronson J, Macor JE, Appiah KK, Westphal RS, O'Connell J, and Gerritz SW
- Subjects
- Amino Acid Sequence, Catalytic Domain, Crystallography, X-Ray, Humans, Hydrophobic and Hydrophilic Interactions, Ligands, Molecular Sequence Data, Protein Binding, Protein Conformation, Receptor-Like Protein Tyrosine Phosphatases, Class 5 chemistry, Structure-Activity Relationship, Thiophenes chemical synthesis, Models, Molecular, Receptor-Like Protein Tyrosine Phosphatases, Class 5 antagonists & inhibitors, Thiophenes chemistry
- Abstract
Protein tyrosine phosphatases (PTPs) catalyze the dephosphorylation of tyrosine residues, a process that involves a conserved tryptophan-proline-aspartate (WPD) loop in catalysis. In previously determined structures of PTPs, the WPD-loop has been observed in either an "open" conformation or a "closed" conformation. In the current work, X-ray structures of the catalytic domain of receptor-like protein tyrosine phosphatase γ (RPTPγ) revealed a ligand-induced "superopen" conformation not previously reported for PTPs. In the superopen conformation, the ligand acts as an apparent competitive inhibitor and binds in a small hydrophobic pocket adjacent to, but distinct from, the active site. In the open and closed WPD-loop conformations of RPTPγ, the side chain of Trp1026 partially occupies this pocket. In the superopen conformation, Trp1026 is displaced allowing a 3,4-dichlorobenzyl substituent to occupy this site. The bound ligand prevents closure of the WPD-loop over the active site and disrupts the catalytic cycle of the enzyme.
- Published
- 2011
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12. Synthesis and antibacterial activity of dihydro-1,2-oxazine and 2-pyrazoline oxazolidinones: novel analogs of linezolid.
- Author
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D'Andrea S, Zheng ZB, Denbleyker K, Fung-Tomc JC, Yang H, Clark J, Taylor D, and Bronson J
- Subjects
- Animals, Gram-Positive Bacteria drug effects, Linezolid, Mice, Microbial Sensitivity Tests, Acetamides chemical synthesis, Acetamides pharmacology, Anti-Bacterial Agents chemical synthesis, Anti-Bacterial Agents pharmacology, Oxazoles chemical synthesis, Oxazoles pharmacology, Oxazolidinones chemical synthesis, Oxazolidinones pharmacology
- Abstract
The synthesis and antibacterial activity of oxazolidinones containing dihydro-1,2-oxazine and 2-pyrazoline ring systems are described. Linezolid analogs utilizing dihydro-1,2-oxazines as morpholine mimics were prepared utilizing a nitrosoamine/diene 4+2 cycloaddition strategy. Pyrazolidine, hexahydro-pyridazine, and 2-pyrazoline analogs more closely related to eperezolid were also prepared. The most active of these new oxazolidinones were the dihydro-1,2-oxazine 6 and the 2-pyrazoline 20 both of which had potency similar to linezolid against a panel of Gram-positive bacteria.
- Published
- 2005
- Full Text
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