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1.
Acta Biomater ; 167: 293-308, 2023 09 01.
Artículo en Inglés | MEDLINE | ID: mdl-37178990

RESUMEN

The extra-cellular matrix (ECM) is a complex and rich microenvironment that is exposed and over-expressed across several injury or disease pathologies. Biomaterial therapeutics are often enriched with peptide binders to target the ECM with greater specificity. Hyaluronic acid (HA) is a major component of the ECM, yet to date, few HA adherent peptides have been discovered. A class of HA binding peptides was designed using B(X7)B hyaluronic acid binding domains inspired from the helical face of the Receptor for Hyaluronic Acid Mediated Motility (RHAMM). These peptides were bioengineered using a custom alpha helical net method, allowing for the enrichment of multiple B(X7)B domains and the optimization of contiguous and non-contiguous domain orientations. Unexpectedly, the molecules also exhibited the behaviour of nanofiber forming self-assembling peptides and were investigated for this characteristic. Ten 23-27 amino acid residue peptides were assessed. Simple molecular modelling was used to depict helical secondary structures. Binding assays were performed with varying concentrations (1-10 mg/mL) and extra-cellular matrices (HA, collagens I-IV, elastin, and Geltrex). Concentration mediated secondary structures were assessed using circular dichroism (CD), and higher order nanostructures were visualized using transmission electron microscopy (TEM). All peptides formed the initial apparent 310/alpha-helices, yet peptides 17x-3, 4, BHP3 and BHP4 were HA specific and potent (i.e., a significant effect) binders at increasing concentrations. These peptides shifted from apparent 310/alpha-helical structures at low concentration to beta-sheets at increasing concentration and also formed nanofibers which are noted as self-assembling structures. Several of the HA binding peptides outperformed our positive control (mPEP35) at 3-4 times higher concentrations, and were enhanced by self-assembly as each of these groups had observable nanofibers. STATEMENT OF SIGNIFICANCE: Specific biomolecules or peptides have played a crucial role in developing materials or systems to deliver key drugs and therapeutics to a broad spectrum of diseases and disorders. In these diseased tissues, cells build protein/sugar networks, which are uniquely exposed and great targets to deliver drugs to. Hyaluronic acid (HA) is involved in every stage of injury and is abundant in cancer. To date, only two HA specific peptides have been discovered. In our work, we have designed a way to model and trace binding regions as they appear on the face of a helical peptide. Using this method we have created a family of peptides enriched with HA binding domains that stick with 3-4 higher affinity than those previously discovered.


Asunto(s)
Ácido Hialurónico , Péptidos , Ácido Hialurónico/metabolismo , Péptidos/química , Proteínas/metabolismo , Proteínas Portadoras/metabolismo , Matriz Extracelular/metabolismo
2.
ACS Med Chem Lett ; 14(2): 163-170, 2023 Feb 09.
Artículo en Inglés | MEDLINE | ID: mdl-36793431

RESUMEN

Acute and chronic pain is often treated with opioids despite the negative side effects of constipation, physical dependence, respiratory depression, and overdose. The misuse of opioid analgesics has given rise to the opioid crisis/epidemic, and alternate nonaddictive analgesics are urgently needed. Oxytocin, a pituitary hormone, is an alternative to the small molecule treatments available and has been used as an analgesic as well as for the treatment and prevention of opioid use disorder (OUD). Clinical implementation is limited by its poor pharmacokinetic profile, a result of the labile disulfide bond between two cysteine residues in the native sequence. Stable brain penetrant oxytocin analogues have been synthesized by replacement of the disulfide bond with a stable lactam and glycosidation of the C-terminus. These analogues show exquisite selectivity for the oxytocin receptor and potent in vivo antinociception in mice following peripheral (i.v.) administration, supporting further study of their clinical potential.

3.
J Med Chem ; 66(1): 677-694, 2023 01 12.
Artículo en Inglés | MEDLINE | ID: mdl-36516003

RESUMEN

A recent study illustrated that a fluorescence polarization assay can be used to identify substrate-competitive Hsp70 inhibitors that can be isoform-selective. Herein, we use that assay in a moderate-throughput screen and report the discovery of a druglike amino-acid-based inhibitor with reasonable specificity for the endoplasmic reticular Hsp70, Grp78. Using traditional medicinal chemistry approaches, the potency and selectivity were further optimized through structure-activity relationship (SAR) studies in parallel assays for six of the human Hsp70 isoforms. The top compounds were all tested against a panel of cancer cell lines and disappointingly showed little effect. The top-performing compound, 8, was retested using a series of endoplasmic reticulum (ER) stress-inducing agents and found to synergize with these agents. Finally, 8 was tested in a spheroid tumor model and found to be more potent than in two-dimensional models. The optimized Grp78 inhibitors are the first reported isoform-selective small-molecule-competitive inhibitors of an Hsp70-substrate interaction.


Asunto(s)
Chaperón BiP del Retículo Endoplásmico , Proteínas de Choque Térmico , Humanos , Proteínas de Choque Térmico/química , Proteínas de Choque Térmico/metabolismo , Proteínas de Choque Térmico/farmacología , Chaperonas Moleculares/química , Proteínas HSP70 de Choque Térmico , Estrés del Retículo Endoplásmico , Isoformas de Proteínas
4.
J Am Chem Soc ; 144(50): 23044-23052, 2022 12 21.
Artículo en Inglés | MEDLINE | ID: mdl-36475699

RESUMEN

A polymerization methodology is reported using sulfur monochloride (S2Cl2) as an alternative feedstock for polymeric materials. S2Cl2 is an inexpensive petrochemical derived from elemental sulfur (S8) but has numerous advantages as a reactive monomer for polymerization vs S8. This new process, termed sulfenyl chloride inverse vulcanization, exploits the high reactivity and miscibility of S2Cl2 with a broad range of allylic monomers to prepare soluble, high molar-mass linear polymers, segmented block copolymers, and crosslinked thermosets with greater synthetic precision than achieved using classical inverse vulcanization. This step-growth addition polymerization also allows for preparation of a new class of thiol-free, inexpensive, highly optically transparent thermosets (α = 0.045 cm-1 at 1310 nm), which exhibit among the best optical transparency and low birefringence relative to commodity optical polymers, while possessing a higher refractive index (n > 1.6) in the visible and near-infrared spectra. The fabrication of large-sized optical components is also demonstrated.


Asunto(s)
Cloruros , Polímeros , Azufre , Luz , Polimerizacion
5.
J Org Chem ; 86(15): 10713-10723, 2021 08 06.
Artículo en Inglés | MEDLINE | ID: mdl-34282910

RESUMEN

A new intramolecular oxidative amino-hydroxylation of o-allenyl anilines is reported. Treatment of carbamate-protected anilines with lead(IV) carboxylates in dichloromethane at room temperature results in facile tandem C-N (allene cyclization) and C-O bond formation (carboxylate trapping) to form indole products. Detailed reaction scope, mechanistic and kinetic studies suggest a reaction pathway involving an initial Wessely dearomatization step followed by cyclization and rearomatization.


Asunto(s)
Compuestos de Anilina , Indoles , Catálisis , Ciclización , Cinética , Estrés Oxidativo
6.
Biomol NMR Assign ; 13(1): 163-167, 2019 04.
Artículo en Inglés | MEDLINE | ID: mdl-30694439

RESUMEN

TAR DNA-binding protein 43 (TDP-43) is a ubiquitously expressed nuclear protein that influences diverse cellular processes by regulating alternative splicing of RNA and microRNA biogenesis. It is also a pathological protein found in sporadic ALS and in the most common subtype of frontotemporal lobar degeneration with ubiquitinated inclusions (FLTD-U). TDP-43 has two tandem RNA-binding domains, RRM1 and RRM2. The NMR structure of TDP-43 was solved in the presence of UG-rich RNA sequences bound to the RRM1 and RRM2 domains. Here we report the backbone assignment of apo TDP-43. The chemical shift (HN, N, C, Cα and Cß) analysis shows the predicted regions of secondary structure are in good agreement with those observed for TDP-43 in complex with RNA. However, our data show that the apo structure of TPD-43 has increased flexibility in the regions that would normally have been used to anchor the RNA bases. The backbone chemical shifts assignments will prove useful in the study of TDP-43 interaction with non-canonical RNA and RRM-binding proteins.


Asunto(s)
Apoproteínas/química , Proteínas de Unión al ADN/química , Resonancia Magnética Nuclear Biomolecular , Motivo de Reconocimiento de ARN , Secuencia de Aminoácidos , Isótopos de Carbono , Humanos , Isótopos de Nitrógeno , Estructura Secundaria de Proteína , Protones
7.
Protein Sci ; 27(10): 1767-1779, 2018 10.
Artículo en Inglés | MEDLINE | ID: mdl-30051937

RESUMEN

New protein folds may evolve from existing folds through metamorphic evolution involving a dramatic switch in structure. To mimic pathways by which amino acid sequence changes could induce a change in fold, we designed two folded hybrids of Xfaso 1 and Pfl 6, a pair of homologous Cro protein sequences with ~40% identity but different folds (all-α vs. α + ß, respectively). Each hybrid, XPH1 or XPH2, is 85% identical in sequence to its parent, Xfaso 1 or Pfl 6, respectively; 55% identical to its noncognate parent; and ~70% identical to the other hybrid. XPH1 and XPH2 also feature a designed hybrid chameleon sequence corresponding to the C-terminal region, which switched from α-helical to ß-sheet structure during Cro evolution. We report solution nuclear magnetic resonance (NMR) structures of XPH1 and XPH2 at 0.3 Å and 0.5 Å backbone root mean square deviation (RMSD), respectively. XPH1 retains a global fold generally similar to Xfaso 1, and XPH2 retains a fold similar to Pfl 6, as measured by TM-align scores (~0.7), DALI Z-scores (7-9), and backbone RMSD (2-3 Å RMSD for the most ordered regions). However, these scores also indicate significant deviations in structure. Most notably, XPH1 and XPH2 have different, and intermediate, secondary structure content relative to Xfaso 1 and Pfl 6. The multistep progression in sequence, from Xfaso 1 to XPH1 to XPH2 to Pfl 6, thus involves both abrupt and gradual changes in folding pattern. The plasticity of some protein folds may allow for "polymetamorphic" evolution through intermediate structures.


Asunto(s)
Proteínas/química , Modelos Moleculares , Mutación , Resonancia Magnética Nuclear Biomolecular , Conformación Proteica , Pliegue de Proteína , Proteínas/genética
8.
Nat Chem Biol ; 14(8): 811-820, 2018 08.
Artículo en Inglés | MEDLINE | ID: mdl-29988068

RESUMEN

Chaperones TAPBPR and tapasin associate with class I major histocompatibility complexes (MHC-I) to promote optimization (editing) of peptide cargo. Here, we use solution NMR to investigate the mechanism of peptide exchange. We identify TAPBPR-induced conformational changes on conserved MHC-I molecular surfaces, consistent with our independently determined X-ray structure of the complex. Dynamics present in the empty MHC-I are stabilized by TAPBPR and become progressively dampened with increasing peptide occupancy. Incoming peptides are recognized according to the global stability of the final pMHC-I product and anneal in a native-like conformation to be edited by TAPBPR. Our results demonstrate an inverse relationship between MHC-I peptide occupancy and TAPBPR binding affinity, wherein the lifetime and structural features of transiently bound peptides control the regulation of a conformational switch located near the TAPBPR binding site, which triggers TAPBPR release. These results suggest a similar mechanism for the function of tapasin in the peptide-loading complex.


Asunto(s)
Regulación Alostérica , Antígenos de Histocompatibilidad Clase I/metabolismo , Inmunoglobulinas/metabolismo , Proteínas de la Membrana/metabolismo , Péptidos/metabolismo , Antígenos de Histocompatibilidad Clase I/química , Humanos , Inmunoglobulinas/química , Proteínas de la Membrana/química , Péptidos/química , Conformación Proteica
9.
Structure ; 25(11): 1687-1696.e4, 2017 11 07.
Artículo en Inglés | MEDLINE | ID: mdl-29033289

RESUMEN

The de novo evolution of protein-coding genes from noncoding DNA is emerging as a source of molecular innovation in biology. Studies of random sequence libraries, however, suggest that young de novo proteins will not fold into compact, specific structures typical of native globular proteins. Here we show that Bsc4, a functional, natural de novo protein encoded by a gene that evolved recently from noncoding DNA in the yeast S. cerevisiae, folds to a partially specific three-dimensional structure. Bsc4 forms soluble, compact oligomers with high ß sheet content and a hydrophobic core, and undergoes cooperative, reversible denaturation. Bsc4 lacks a specific quaternary state, however, existing instead as a continuous distribution of oligomer sizes, and binds dyes indicative of amyloid oligomers or molten globules. The combination of native-like and non-native-like properties suggests a rudimentary fold that could potentially act as a functional intermediate in the emergence of new folded proteins de novo.


Asunto(s)
ADN Intergénico/química , Proteínas de Saccharomyces cerevisiae/química , Saccharomyces cerevisiae/metabolismo , Secuencia de Aminoácidos , Clonación Molecular , ADN Intergénico/genética , ADN Intergénico/metabolismo , Escherichia coli/genética , Escherichia coli/metabolismo , Vectores Genéticos/química , Vectores Genéticos/metabolismo , Interacciones Hidrofóbicas e Hidrofílicas , Cinética , Biosíntesis de Proteínas , Conformación Proteica en Lámina beta , Desnaturalización Proteica , Pliegue de Proteína , Multimerización de Proteína , Proteínas Recombinantes/química , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Saccharomyces cerevisiae/genética , Proteínas de Saccharomyces cerevisiae/genética , Proteínas de Saccharomyces cerevisiae/metabolismo , Alineación de Secuencia , Homología de Secuencia de Aminoácido , Termodinámica
10.
J Heterocycl Chem ; 54(2): 1228-1235, 2017 03.
Artículo en Inglés | MEDLINE | ID: mdl-28819330

RESUMEN

Several studies have suggested functional association between µ-opioid and δ-opioid receptors and showed that µ-activity could be modulated by δ-ligands. The general conclusion is that agonists for the δ-receptor can enhance the analgesic potency and efficacy of µ-agonists. Our preliminary investigations demonstrate that new bivalent ligands constructed from the µ-agonist fentanyl and the δ-agonist enkephalin-like peptides are promising entities for creation of new analgesics with reduced side effects for treatment of neuropathic pain. A new superposition of the mentioned pharmacophores led to novel µ-bivalent/δ-bivalent compounds that demonstrate both µ-opioid and δ-opioid receptor agonist activity and high efficacy in anti-inflammatory and neuropathic pain models with the potential of reduced unwanted side effects.

11.
Nat Commun ; 8: 15260, 2017 05 16.
Artículo en Inglés | MEDLINE | ID: mdl-28508865

RESUMEN

The molecular mechanism through which the interaction of a clonotypic αß T-cell receptor (TCR) with a peptide-loaded major histocompatibility complex (p/MHC) leads to T-cell activation is not yet fully understood. Here we exploit a high-affinity TCR (B4.2.3) to examine the structural changes that accompany binding to its p/MHC ligand (P18-I10/H2-Dd). In addition to conformational changes in complementarity-determining regions (CDRs) of the TCR seen in comparison of unliganded and bound X-ray structures, NMR characterization of the TCR ß-chain dynamics reveals significant chemical shift effects in sites removed from the MHC-binding site. Remodelling of electrostatic interactions near the Cß H3 helix at the membrane-proximal face of the TCR, a region implicated in interactions with the CD3 co-receptor, suggests a possible role for an allosteric mechanism in TCR signalling. The contribution of these TCR residues to signal transduction is supported by mutagenesis and T-cell functional assays.


Asunto(s)
Sitio Alostérico/inmunología , Regiones Determinantes de Complementariedad/química , Receptores de Antígenos de Linfocitos T alfa-beta/química , Transducción de Señal/inmunología , Linfocitos T/inmunología , Animales , Regiones Determinantes de Complementariedad/metabolismo , Cristalografía por Rayos X , Complejo Mayor de Histocompatibilidad/inmunología , Ratones , Simulación de Dinámica Molecular , Mutagénesis , Péptidos/metabolismo , Unión Proteica/inmunología , Dominios Proteicos/inmunología , Receptores de Antígenos de Linfocitos T alfa-beta/genética , Receptores de Antígenos de Linfocitos T alfa-beta/inmunología , Receptores de Antígenos de Linfocitos T alfa-beta/metabolismo , Linfocitos T/metabolismo
12.
Protein Eng Des Sel ; 28(8): 241-50, 2015 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-25991865

RESUMEN

To study the sequence determinants governing protein fold evolution, we generated hybrid sequences from two homologous proteins with 40% identity but different folds: Pfl 6 Cro, which has a mixed α + ß structure, and Xfaso 1 Cro, which has an all α-helical structure. First, we first examined eight chimeric hybrids in which the more structurally conserved N-terminal half of one protein was fused to the more structurally divergent C-terminal half of the other. None of these chimeras folded, as judged by circular dichroism spectra and thermal melts, suggesting that both halves have strong intrinsic preferences for the native global fold pattern, and/or that the interfaces between the halves are not readily interchangeable. Second, we examined 10 hybrids in which blocks of the structurally divergent C-terminal region were exchanged. These hybrids showed varying levels of thermal stability and suggested that the key residues in the Xfaso 1 C terminus specifying the all-α fold were concentrated near the end of helix 4 in Xfaso 1, which aligns to the end of strand 2 in Pfl 6. Finally, we generated hybrid substitutions for each individual residue in this critical region and measured thermal stabilities. The results suggested that R47 and V48 were the strongest factors that excluded formation of the α + ß fold in the C-terminal region of Xfaso 1. In support of this idea, we found that the folding stability of one of the original eight chimeras could be rescued by back-substituting these two residues. Overall, the results show not only that the key factors for Cro fold specificity and evolution are global and multifarious, but also that some all-α Cro proteins have a C-terminal subdomain sequence within a few substitutions of switching to the α + ß fold.


Asunto(s)
Evolución Molecular Dirigida , Pliegue de Proteína , Proteínas Recombinantes de Fusión/química , Estabilidad Proteica , Estructura Secundaria de Proteína , Estructura Terciaria de Proteína , Proteínas Recombinantes de Fusión/genética
13.
Life Sci ; 93(25-26): 1010-6, 2013 Dec 18.
Artículo en Inglés | MEDLINE | ID: mdl-24084045

RESUMEN

UNLABELLED: Approximately one third of the adult U.S. population suffers from some type of on-going, chronic pain annually, and many more will have some type of acute pain associated with trauma or surgery. First-line therapies for moderate to severe pain include prescriptions for common mu opioid receptor agonists such as morphine and its various derivatives. The epidemic use, misuse and diversion of prescription opioids have highlighted just one of the adverse effects of mu opioid analgesics. Alternative approaches include novel opioids that target delta or kappa opioid receptors, or compounds that interact with two or more of the opioid receptors. AIMS: Here we report the pharmacology of a newly synthesized bifunctional opioid agonist (RV-Jim-C3) derived from combined structures of fentanyl and enkephalin in rodents. RV-Jim-C3 has high affinity binding to both mu and delta opioid receptors. MAIN METHODS: Mice and rats were used to test RV-Jim-C3 in a tailflick test with and without opioid selective antagonist for antinociception. RV-Jim-C3 was tested for anti-inflammatory and antihypersensitivity effects in a model of formalin-induced flinching and spinal nerve ligation. To rule out motor impairment, rotarod was tested in rats. KEY FINDINGS: RV-Jim-C3 demonstrates potent-efficacious activity in several in vivo pain models including inflammatory pain, antihyperalgesia and antiallodynic with no significant motor impairment. SIGNIFICANCE: This is the first report of a fentanyl-based structure with delta and mu opioid receptor activity that exhibits outstanding antinociceptive efficacy in neuropathic pain, reducing the propensity of unwanted side effects driven by current therapies that are unifunctional mu opioid agonists.


Asunto(s)
Dolor Agudo/tratamiento farmacológico , Analgésicos Opioides/farmacología , Dolor Crónico/tratamiento farmacológico , Encefalinas/farmacología , Fentanilo/análogos & derivados , Fentanilo/química , Receptores Opioides delta/agonistas , Receptores Opioides mu/agonistas , Analgésicos Opioides/química , Analgésicos Opioides/metabolismo , Animales , Antiinflamatorios no Esteroideos/farmacología , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Evaluación Preclínica de Medicamentos/métodos , Encefalinas/química , Fentanilo/farmacología , Masculino , Ratones , Ratones Endogámicos ICR , Naloxona/farmacología , Naltrexona/análogos & derivados , Naltrexona/farmacología , Antagonistas de Narcóticos/farmacología , Ratas , Ratas Sprague-Dawley , Receptores Opioides delta/metabolismo , Receptores Opioides mu/metabolismo
14.
PLoS One ; 8(8): e72372, 2013.
Artículo en Inglés | MEDLINE | ID: mdl-24009677

RESUMEN

Venoms of brown spiders in the genus Loxosceles contain phospholipase D enzyme toxins that can cause severe dermonecrosis and even death in humans. These toxins cleave the substrates sphingomyelin and lysophosphatidylcholine in mammalian tissues, releasing the choline head group. The other products of substrate cleavage have previously been reported to be monoester phospholipids, which would result from substrate hydrolysis. Using (31)P NMR and mass spectrometry we demonstrate that recombinant toxins, as well as whole venoms from diverse Loxosceles species, exclusively catalyze transphosphatidylation rather than hydrolysis, forming cyclic phosphate products from both major substrates. Cyclic phosphates have vastly different biological properties from their monoester counterparts, and they may be relevant to the pathology of brown spider envenomation.


Asunto(s)
Lisofosfatidilcolinas/química , Fosfatos/química , Fosfolipasa D/química , Esfingomielinas/química , Venenos de Araña/química , Animales , Araña Reclusa Parda/química , Espectrometría de Masas , Fosfolipasa D/metabolismo , Proteínas Recombinantes/química , Proteínas Recombinantes/metabolismo , Especificidad por Sustrato
15.
Bioorg Med Chem ; 19(20): 6135-42, 2011 Oct 15.
Artículo en Inglés | MEDLINE | ID: mdl-21925887

RESUMEN

Newly designed bivalent ligands-opioid agonist/NK1-antagonists have been synthesized. The synthesis of new starting materials-carboxy-derivatives of Fentanyl (1a-1c) was developed. These products have been transformed to 'isoimidium perchlorates' (2a-c). The new isoimidium perchlorates have been successfully implemented in nucleophilic addition reactions, with l-tryptophan 3,5-bis(trifluoromethyl)benzyl ester to give the target compounds-amides (3a-c). Perchlorates (2a-c) successfully undergo reactions with other nucleophiles such as alcohols, amines or hydrazines. The obtained compound 3b exhibited µ-opioid agonist activity and NK1-antagonist activity and may serve as a useful lead compound for the further design of a new series of opioid agonist/NK1-antagonist compounds.


Asunto(s)
Analgésicos Opioides/síntesis química , Analgésicos Opioides/farmacología , Antagonistas del Receptor de Neuroquinina-1 , Analgésicos Opioides/química , Animales , Sitios de Unión , Diseño de Fármacos , Cobayas , Humanos , Ligandos , Masculino , Ratones , Ratones Endogámicos ICR , Receptores de Neuroquinina-1/metabolismo
16.
CrystEngComm ; 12(11): 3651-3657, 2010.
Artículo en Inglés | MEDLINE | ID: mdl-25425961

RESUMEN

Three compounds, each derived from Fentanyl and differing essentially only in the length of a carboxylic acid chain, were synthesized and yielded four crystal structures three of which share several structural similarities, including the length of the chain, while the fourth, with a shorter chain, is quite different. The chain length has a significant influence on the crystal structures formed. The 'three atom' chain compounds are all solvated zwitterions which feature a hydrogen-bonded 'dimer' between adjacent zwitterions. The formation of this large dimer leaves available a second carboxylate O atom to take part in hydrogen bonding interactions with solvent molecules. The shorter 'two atom' chain compound was difficult to crystallize and required the use of synchrotron radiation to measure X-ray diffraction data. It does not form the same dimer motif observed in the 'three atom' chain compounds and has not formally formed a zwitterion; although there is evidence of proton sharing or disorder X-ray data are insufficient to create a disordered model, and the compound was modeled as formally neutral based on O-H and N-H distances. Room temperature analyses showed the proton transfer behavior to be independent of crystal temperature, and nuclear magnetic resonance studies show proton transfer behavior in solution. The formation of a zwitterionic hydrogen-bonded dimer is implicated in providing some stability during crystal growth of the easily crystallized 'three atom' chain compounds.

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