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Open AccessArticle
Expression of FGF8, FGF18, and FGFR4 in Gastroesophageal Adenocarcinomas
Cells 2019, 8(9), 1092; https://doi.org/10.3390/cells8091092 (registering DOI) - 16 Sep 2019
Abstract
Even though distinctive advances in the field of esophageal cancer therapy have occurred over the last few years, patients’ survival rates remain poor. FGF8, FGF18, and FGFR4 have been identified as promising biomarkers in a number of cancers; however no data exist on [...] Read more.
Even though distinctive advances in the field of esophageal cancer therapy have occurred over the last few years, patients’ survival rates remain poor. FGF8, FGF18, and FGFR4 have been identified as promising biomarkers in a number of cancers; however no data exist on expression of FGF8, FGF18, and FGFR4 in adenocarcinomas of the esophago-gastric junction (AEG). A preliminary analysis of the Cancer Genome Atlas (TCGA) database on FGF8, FGF18, and FGFR4 mRNA expression data of patients with AEG was performed. Furthermore, protein levels of FGF8, FGF18, and FGFR4 in diagnostic biopsies and post-operative specimens in neoadjuvantly treated and primarily resected patients using immunohistochemistry were investigated. A total of 242 patients was analyzed in this study: 87 patients were investigated in the TCGA data set analysis and 155 patients in the analysis of protein expression using immunohistochemistry. High protein levels of FGF8, FGF18, and FGFR4 were detected in 94 (60.7%), 49 (31.6%) and 84 (54.2%) patients, respectively. Multivariable Cox proportional hazard regression models revealed that high expression of FGF8 was an independent prognostic factor for diminished overall survival for all patients and for neoadjuvantly treated patients. By contrast, FGF18 overexpression was significantly associated with longer survival rates in neoadjuvantly treated patients. In addition, FGF8 protein level correlated with Mandard regression due to neoadjuvant therapy, indicating potential as a predictive marker. In summary, FGF8 and FGF18 are promising candidates for prognostic factors in adenocarcinomas of the esophago-gastric junction and new potential targets for new anti-cancer therapies. Full article
(This article belongs to the Special Issue Fibroblast Growth Factor Receptor (FGFR) Signaling Pathway in Tumor)
Open AccessArticle
MALDI-MSI as a Complementary Diagnostic Tool in Cytopathology: A Pilot Study for the Characterization of Thyroid Nodules
Cancers 2019, 11(9), 1377; https://doi.org/10.3390/cancers11091377 (registering DOI) - 16 Sep 2019
Abstract
The present study applies for the first time as Matrix-Assisted Laser Desorption/Ionization (MALDI) Mass Spectrometry Imaging (MSI) on real thyroid Fine Needle Aspirations (FNAs) to test its possible complementary role in routine cytology in the diagnosis of thyroid nodules. The primary aim is [...] Read more.
The present study applies for the first time as Matrix-Assisted Laser Desorption/Ionization (MALDI) Mass Spectrometry Imaging (MSI) on real thyroid Fine Needle Aspirations (FNAs) to test its possible complementary role in routine cytology in the diagnosis of thyroid nodules. The primary aim is to evaluate the potential employment of MALDI-MSI in cytopathology, using challenging samples such as needle washes. Firstly, we designed a statistical model based on the analysis of Regions of Interest (ROIs), according to the morphological triage performed by the pathologist. Successively, the capability of the model to predict the classification of the FNAs was validated in a different group of patients on ROI and pixel-by-pixel approach. Results are very promising and highlight the possibility to introduce MALDI-MSI as a complementary tool for the diagnostic characterization of thyroid nodules. Full article
(This article belongs to the Special Issue Thyroid Cancer)
Open AccessArticle
Multiscale Study of Interactions Between Corrosion Products Layer Formed on Heritage Cu Objects and Organic Protection Treatments
Heritage 2019, 2(3), 2640-2651; https://doi.org/10.3390/heritage2030162 (registering DOI) - 16 Sep 2019
Abstract
In the framework of the protection of copper objects exposed to atmospheric corrosion, different solutions are envisaged, among them carboxylate treatments (HC10). In this study, an analytical approach based on complementary techniques from micrometer to nanometer scale (μRS, SEM-EDS, SAM) is [...] Read more.
In the framework of the protection of copper objects exposed to atmospheric corrosion, different solutions are envisaged, among them carboxylate treatments (HC10). In this study, an analytical approach based on complementary techniques from micrometer to nanometer scale (μRS, SEM-EDS, SAM) is used to describe the properties of the corrosion products layer (CPL) and determine the penetration depth of the HC10 protection treatment inside the CPL of copper samples issued from the roof of the Saint Martin church in Metz. The CPL consists in a thick brochantite layer (20 to 50 μm), mainly composed of Cu4SO4(OH)6, on top of a thinner (1 to 5 μm thick) cuprite layer, Cu2O, acting as a natural corrosion barrier on the metal. Application of the organic treatment is implemented by immersing the corroded samples in HC10 solution, consistent with future requirements for large scale applications. Even for short-term duration (one minute), the HC10 treatment penetrates to the cuprite/brochantite interface, but Cu(C10)2 precipitate is only detected locally, whereas for a longer immersion of thirty minutes, it is present in higher proportions in the whole brochantite layer, filling the pores, up to the cuprite/brochantite interface. Cu(C10)2 acts as a second inner barrier and prevents liquid infiltration. Full article
(This article belongs to the Special Issue Cultural Heritage—Science, Materials and Technologies)
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Open AccessReview
Predictive Power of In Silico Approach to Evaluate Chemicals against M. tuberculosis: A Systematic Review
Pharmaceuticals 2019, 12(3), 135; https://doi.org/10.3390/ph12030135 (registering DOI) - 16 Sep 2019
Abstract
Mycobacterium tuberculosis (Mtb) is an endemic bacterium worldwide that causes tuberculosis (TB) and involves long-term treatment that is not always effective. In this context, several studies are trying to develop and evaluate new substances active against Mtb. In silico techniques are often used [...] Read more.
Mycobacterium tuberculosis (Mtb) is an endemic bacterium worldwide that causes tuberculosis (TB) and involves long-term treatment that is not always effective. In this context, several studies are trying to develop and evaluate new substances active against Mtb. In silico techniques are often used to predict the effects on some known target. We used a systematic approach to find and evaluate manuscripts that applied an in silico technique to find antimycobacterial molecules and tried to prove its predictive potential by testing them in vitro or in vivo. After searching three different databases and applying exclusion criteria, we were able to retrieve 46 documents. We found that they all follow a similar screening procedure, but few studies exploited equal targets, exploring the interaction of multiple ligands to 29 distinct enzymes. The following in vitro/vivo analysis showed that, although the virtual assays were able to decrease the number of molecules tested, saving time and money, virtual screening procedures still need to develop the correlation to more favorable in vitro outcomes. We find that the in silico approach has a good predictive power for in vitro results, but call for more studies to evaluate its clinical predictive possibilities. Full article
(This article belongs to the Special Issue New Tools for Medicinal Chemists)
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Open AccessFeature PaperArticle
Structure-Function Elucidation of a New α-Conotoxin, MilIA, from Conus milneedwardsi
Mar. Drugs 2019, 17(9), 535; https://doi.org/10.3390/md17090535 (registering DOI) - 16 Sep 2019
Abstract
The a-Conotoxins are peptide toxins that are found in the venom of marine cone snails and they are potent antagonists of various subtypes of nicotinic acetylcholine receptors (nAChRs). Because nAChRs have an important role in regulating transmitter release, cell excitability, and neuronal integration, [...] Read more.
The a-Conotoxins are peptide toxins that are found in the venom of marine cone snails and they are potent antagonists of various subtypes of nicotinic acetylcholine receptors (nAChRs). Because nAChRs have an important role in regulating transmitter release, cell excitability, and neuronal integration, nAChR dysfunctions have been implicated in a variety of severe pathologies. We describe the isolation and characterization of α-conotoxin MilIA, the first conopeptide from the venom of Conus milneedwardsi. The peptide was characterized by electrophysiological screening against several types of cloned nAChRs that were expressed in Xenopus laevis oocytes. MilIA, which is a member of the α3/5 family, is an antagonist of muscle type nAChRs with a high selectivity for muscle versus neuronal subtype nAChRs. Several analogues were designed and investigated for their activity in order to determine the key epitopes of MilIA. Native MilIA and analogues both showed activity at the fetal muscle type nAChR. Two single mutations (Met9 and Asn10) allowed for MilIA to strongly discriminate between the two types of muscle nAChRs. Moreover, one analogue, MilIA [∆1,M2R, M9G, N10K, H11K], displayed a remarkable enhanced potency when compared to native peptide. The key residues that are responsible for switching between muscle and neuronal nAChRs preference were elucidated. Interestingly, the same analogue showed a preference for α9α10 nAChRs among the neuronal types. Full article
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Open AccessReview
Equol: A Bacterial Metabolite from The Daidzein Isoflavone and Its Presumed Beneficial Health Effects
Nutrients 2019, 11(9), 2231; https://doi.org/10.3390/nu11092231 (registering DOI) - 16 Sep 2019
Abstract
Epidemiological data suggest that regular intake of isoflavones from soy reduces the incidence of estrogen-dependent and aging-associated disorders, such as menopause symptoms in women, osteoporosis, cardiovascular diseases and cancer. Equol, produced from daidzein, is the isoflavone-derived metabolite with the greatest estrogenic and antioxidant [...] Read more.
Epidemiological data suggest that regular intake of isoflavones from soy reduces the incidence of estrogen-dependent and aging-associated disorders, such as menopause symptoms in women, osteoporosis, cardiovascular diseases and cancer. Equol, produced from daidzein, is the isoflavone-derived metabolite with the greatest estrogenic and antioxidant activity. Consequently, equol has been endorsed as having many beneficial effects on human health. The conversion of daidzein into equol takes place in the intestine via the action of reductase enzymes belonging to incompletely characterized members of the gut microbiota. While all animal species analyzed so far produce equol, only between one third and one half of human subjects (depending on the community) are able to do so, ostensibly those that harbor equol-producing microbes. Conceivably, these subjects might be the only ones who can fully benefit from soy or isoflavone consumption. This review summarizes current knowledge on the microorganisms involved in, the genetic background to, and the biochemical pathways of, equol biosynthesis. It also outlines the results of recent clinical trials and meta-analyses on the effects of equol on different areas of human health and discusses briefly its presumptive mode of action. Full article
(This article belongs to the Special Issue Dietary Bioactive Compounds and Human Health and Disease)
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Open AccessFeature PaperArticle
Numerical Integral Transform Methods for Random Hyperbolic Models with a Finite Degree of Randomness
Mathematics 2019, 7(9), 853; https://doi.org/10.3390/math7090853 (registering DOI) - 16 Sep 2019
Abstract
This paper deals with the construction of numerical solutions of random hyperbolic models with a finite degree of randomness that make manageable the computation of its expectation and variance. The approach is based on the combination of the random Fourier transforms, the random [...] Read more.
This paper deals with the construction of numerical solutions of random hyperbolic models with a finite degree of randomness that make manageable the computation of its expectation and variance. The approach is based on the combination of the random Fourier transforms, the random Gaussian quadratures and the Monte Carlo method. The recovery of the solution of the original random partial differential problem throughout the inverse integral transform allows its numerical approximation using Gaussian quadratures involving the evaluation of the solution of the random ordinary differential problem at certain concrete values, which are approximated using Monte Carlo method. Numerical experiments illustrating the numerical convergence of the method are included. Full article
(This article belongs to the Special Issue Stochastic Differential Equations and Their Applications)
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Open AccessArticle
Novel Edible Coating with Antioxidant and Antimicrobial Activities Based on Whey Protein Isolate Nanofibrils and Carvacrol and Its Application on Fresh-Cut Cheese
Coatings 2019, 9(9), 583; https://doi.org/10.3390/coatings9090583 (registering DOI) - 16 Sep 2019
Abstract
The composition and properties of edible coatings (ECs) will significantly influence their effects of food preservation. For the first time, whey protein isolates nanofibers (WPNFs), as a novel material with high hydrophobicity and antioxidant activity, combined with carvacrol (CA) as an antimicrobial agent [...] Read more.
The composition and properties of edible coatings (ECs) will significantly influence their effects of food preservation. For the first time, whey protein isolates nanofibers (WPNFs), as a novel material with high hydrophobicity and antioxidant activity, combined with carvacrol (CA) as an antimicrobial agent and glycerol (Gly) as a plasticizer, was used to prepare edible coating (WPNFs-CA/Gly) for preserving fresh-cut Cheddar cheese. The prepared WPNFs and ECs emulsions have been investigated with transmission electron microscopy. Furthermore, the antioxidant activity of ECs emulsions, antimicrobial activity of edible films, and the physical properties of edible films, such as micromorphology, thickness, transparency, and moisture content, have also been evaluated. The weight losses and physical characteristics of both coated and uncoated fresh-cut Cheddar cheese samples have been assessed during storage. The DPPH free radical scavenging rate of WPNFs-CA/Gly emulsion was up to 67.89% and the reducing power was 0.821, which was higher than that of WPI-CA/Gly emulsions. The antimicrobial activity of WPNFs-CA/Gly films was nearly 2.0-fold higher than that of WPNFs/Gly films for the presence of CA. The WPNFs-CA/Gly films had smooth and continuous surfaces, and the transparency reached 49.7% and the moisture content was 26.0%, which was better than that of WPI-CA/Gly films. Furthermore, Cheddar cheese with WPNFs-CA/Gly coatings has shown lower weight losses (15.23%) and better textural properties than those uncoated samples. This in-depth study has provided a valuable and noteworthy approach about the novel edible coating material. Full article
(This article belongs to the Special Issue Edible Films and Coatings: Fundamentals and Applications)
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Open AccessArticle
Induction of Redox-Active Gene Expression by CoCl2 Ameliorates Oxidative Stress-Mediated Injury of Murine Auditory Cells
Antioxidants 2019, 8(9), 399; https://doi.org/10.3390/antiox8090399 (registering DOI) - 16 Sep 2019
Abstract
Free radicals formed in the inner ear in response to high-intensity noise, are regarded as detrimental factors for noise-induced hearing loss (NIHL). We reported previously that intraperitoneal injection of cobalt chloride attenuated the loss of sensory hair cells and NIHL in mice. The [...] Read more.
Free radicals formed in the inner ear in response to high-intensity noise, are regarded as detrimental factors for noise-induced hearing loss (NIHL). We reported previously that intraperitoneal injection of cobalt chloride attenuated the loss of sensory hair cells and NIHL in mice. The present study was designed to understand the preconditioning effect of CoCl2 on oxidative stress-mediated cytotoxicity. Treatment of auditory cells with CoCl2 promoted cell proliferation, with increases in the expressions of two redox-active transcription factors (hypoxia-inducible factor 1α, HIF-1α, nuclear factor erythroid 2-related factor 2; Nrf-2) and an antioxidant enzyme (peroxiredoxin 6, Prdx6). Hydrogen peroxide treatment resulted in the induction of cell death and reduction of these protein expressions, reversed by pretreatment with CoCl2. Knockdown of HIF-1α or Nrf-2 attenuated the preconditioning effect of CoCl2. Luciferase reporter analysis with a Prdx6 promoter revealed transactivation of Prdx6 expression by HIF-1α and Nrf-2. The intense immunoreactivities of HIF-1α, Nrf-2, and Prdx6 in the organ of Corti (OC), spiral ganglion cells (SGC), and stria vascularis (SV) of the cochlea in CoCl2-injected mice suggested CoCl2-induced activation of HIF-1α, Nrf-2, and Prdx6 in vivo. Therefore, we revealed that the protective effect of CoCl2 is achieved through distinctive signaling mechanisms involving HIF-1α, Nrf-2, and Prdx6. Full article
(This article belongs to the Section Antioxidant Enzyme Systems)
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Open AccessArticle
Development and Validation of a Virtual Gelatin Model Using Molecular Modeling Computational Tools
Molecules 2019, 24(18), 3365; https://doi.org/10.3390/molecules24183365 (registering DOI) - 16 Sep 2019
Abstract
To successfully design and optimize the application of hydrogel matrices one has to effectively combine computational design tools with experimental methods. In this context, one of the most promising techniques is molecular modeling, which requires however accurate molecular models representing the investigated material. [...] Read more.
To successfully design and optimize the application of hydrogel matrices one has to effectively combine computational design tools with experimental methods. In this context, one of the most promising techniques is molecular modeling, which requires however accurate molecular models representing the investigated material. Although this method has been successfully used over the years for predicting the properties of polymers, its application to biopolymers, including gelatin, is limited. In this paper we provide a method for creating an atomistic representation of gelatin based on the modified FASTA codes of natural collagen. We show that the model created in this manner reproduces known experimental values of gelatin properties like density, glass-rubber transition temperature, WAXS profile and isobaric thermal expansion coefficient. We also present that molecular dynamics using the INTERFACE force field provides enough accuracy to track changes of density, fractional free volume and Hansen solubility coefficient over a narrow temperature regime (273–318 K) with 1 K accuracy. Thus we depict that using molecular dynamics one can predict properties of gelatin biopolymer as an efficient matrix for immobilization of various bioactive compounds, including enzymes. Full article
(This article belongs to the Special Issue Gelatin: Chemistry, Characterization, Application)
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Open AccessFeature PaperArticle
Expression of FGFR1–4 in Malignant Pleural Mesothelioma Tissue and Corresponding Cell Lines and its Relationship to Patient Survival and FGFR Inhibitor Sensitivity
Cells 2019, 8(9), 1091; https://doi.org/10.3390/cells8091091 (registering DOI) - 16 Sep 2019
Abstract
Malignant pleural mesothelioma (MPM) is a devastating malignancy with limited therapeutic options. Fibroblast growth factor receptors (FGFR) and their ligands were shown to contribute to MPM aggressiveness and it was suggested that subgroups of MPM patients could benefit from FGFR-targeted inhibitors. In the [...] Read more.
Malignant pleural mesothelioma (MPM) is a devastating malignancy with limited therapeutic options. Fibroblast growth factor receptors (FGFR) and their ligands were shown to contribute to MPM aggressiveness and it was suggested that subgroups of MPM patients could benefit from FGFR-targeted inhibitors. In the current investigation, we determined the expression of all four FGFRs (FGFR1–FGFR4) by immunohistochemistry in tissue samples from 94 MPM patients. From 13 of these patients, we were able to establish stable cell lines, which were subjected to FGFR1–4 staining, transcript analysis by quantitative RT-PCR, and treatment with the FGFR inhibitor infigratinib. While FGFR1 and FGFR2 were widely expressed in MPM tissue and cell lines, FGFR3 and FGFR4 showed more restricted expression. FGFR1 and FGFR2 showed no correlation with clinicopathologic data or patient survival, but presence of FGFR3 in 42% and of FGFR4 in 7% of patients correlated with shorter overall survival. Immunostaining in cell lines was more homogenous than in the corresponding tissue samples. Neither transcript nor protein expression of FGFR1–4 correlated with response to infigratinib treatment in MPM cell lines. We conclude that FGFR3 and FGFR4, but not FGFR1 or FGFR2, have prognostic significance in MPM and that FGFR expression is not sufficient to predict FGFR inhibitor response in MPM cell lines. Full article
(This article belongs to the Special Issue Fibroblast Growth Factor Receptor (FGFR) Signaling Pathway in Tumor)
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Open AccessArticle
Effect of Nanocrystallization of Anthocyanins Extracted from Two Types of Red-Fleshed Apple Varieties on Its Stability and Antioxidant Activity
Molecules 2019, 24(18), 3366; https://doi.org/10.3390/molecules24183366 (registering DOI) - 16 Sep 2019
Abstract
Red-fleshed apple (Malus sieversii f. neidzwetzkyana (Dieck) Langenf) has attracted more and more attention due to its enriched anthocyanins and high antioxidant activity. In this study we extracted total anthocyanins and phenols from two types of red-fleshed apples—Xinjing No.4 (XJ4) and Red [...] Read more.
Red-fleshed apple (Malus sieversii f. neidzwetzkyana (Dieck) Langenf) has attracted more and more attention due to its enriched anthocyanins and high antioxidant activity. In this study we extracted total anthocyanins and phenols from two types of red-fleshed apples—Xinjing No.4 (XJ4) and Red Laiyang (RL)—to study the stability and antioxidant activity of anthocyanins after encapsulation onto Corn Starch Nanoparticles (CSNPs). The results indicated the anthocyanins and total phenol levels of XJ4 were 2.96 and 2.25 times higher than those of RL respectively. The anthocyanin concentration and loading time had a significant effect on CSNPs encapsulation, and XJ4 anthocyanins always showed significantly higher loading capacity than RL. After encapsulation, the morphology of RL-CSNPs and XJ4-CSNPs was still spherical with a smooth surface as CSNPs, but the particle size increased compared to CSNPs especially for RL-CSNPs. Different stress treatments including UV light, pH, temperature, and salinity suggested that XJ4-CSNPs exhibited consistently higher stability than RL-CSNPs. A significantly enhanced free radical scavenging rate under stress conditions was observed, and XJ4-CSNPs had stronger antioxidant activity than RL-CSNPs. Furthermore, XJ4-CSNPs exhibited a slower released rate than RL-CSNPs in simulated gastric (pH 2.0) and intestinal (pH 7.0) environments. Our research suggests that nanocrystallization of anthocyanins is an effective method to keep the anthocyanin ingredients intact and active while maintaining a slow release rate. Compared to RL, encapsulation of XJ4 anthocyanins has more advantages, which might be caused by the significant differences in the metabolites of XJ4. These findings give an insight into understanding the role of nanocrystallization using CSNPs in enhancing the antioxidant ability of anthocyanins from different types of red-fleshed apples, and provide theoretical foundations for red-fleshed apple anthocyanin application. Full article
(This article belongs to the Special Issue Antioxidants Chemistry and Applications)
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Open AccessArticle
Prebiotic Peptide Bond Formation Through Amino Acid Phosphorylation. Insights from Quantum Chemical Simulations
Life 2019, 9(3), 75; https://doi.org/10.3390/life9030075 (registering DOI) - 16 Sep 2019
Abstract
Condensation reactions between biomolecular building blocks are the main synthetic channels to build biopolymers. However, under highly diluted prebiotic conditions, condensations are thermodynamically hampered since they release water. Moreover, these reactions are also kinetically hindered as, in the absence of any catalyst, they [...] Read more.
Condensation reactions between biomolecular building blocks are the main synthetic channels to build biopolymers. However, under highly diluted prebiotic conditions, condensations are thermodynamically hampered since they release water. Moreover, these reactions are also kinetically hindered as, in the absence of any catalyst, they present high activation energies. In living organisms, in the formation of peptides by condensation of amino acids, this issue is overcome by the participation of adenosine triphosphate (ATP), in which, previous to the condensation, phosphorylation of one of the reactants is carried out to convert it as an activated intermediate. In this work, we present for the first time results based on density functional theory (DFT) calculations on the peptide bond formation between two glycine (Gly) molecules adopting this phosphorylation-based mechanism considering a prebiotic context. Here, ATP has been modeled by a triphosphate (TP) component, and different scenarios have been considered: (i) gas-phase conditions, (ii) in the presence of a Mg2+ ion available within the layer of clays, and (iii) in the presence of a Mg2+ ion in watery environments. For all of them, the free energy profiles have been fully characterized. Energetics derived from the quantum chemical calculations indicate that none of the processes seem to be feasible in the prebiotic context. In scenarios (i) and (ii), the reactions are inhibited due to unfavorable thermodynamics associated with the formation of high energy intermediates, while in scenario (iii), the reaction is inhibited due to the high free energy barrier associated with the condensation reactions. As a final consideration, the role of clays in this TP-mediated peptide bond formation route is advocated, since the interaction of the phosphorylated intermediate with the internal clay surfaces could well favor the reaction free energies. Full article
(This article belongs to the Section Origin of Life)
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