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Back to Journal »International Journal of Nanomedicine» Volume 16

Boron Nitride Nanotubes as Carriers for Antimicrobial Peptides: Theoretical Insights

Author Zarghami Dehaghani M, Bagheri B, Yousefi F, Nasiriasayesh A, Hamed Mashhadzadeh A, Zarrintaj P, Rabiee N, Bagherzadeh M, Fierro V, Celzard A, Saeb MR, Mostafavi E 

Published on March 4, 2021, Volume 2021: 16 pages, 1837—1847

DOI https://doi.org/10.2147/IJN.S298699

Single anonymous peer review

Editor approved for publication: Professor Israel (Rudi) Rubinstein

Maryam Zarghami Dehaghani,1,* Babak Bagheri,2,* Farrokh Yousefi,3 Abbasali Nasiriasayesh,4 Amin Hamed Mashhadzadeh,5 Payam Zarrintaj,6 Navid Rabiee,7 Mojtaba Bagherzadeh,7 Vanessa Fierro,8 A9 Celbrad, Saafavilain Celbrad, Saafeb 5 Most 10 1 School of Chemical Engineering, Faculty of Engineering, Tehran University, Tehran, Iran; 2 Department of Chemistry and Biomolecular Engineering, Korea Institute of Advanced Science and Technology (KAIST), Daejeon, South Korea; 3 Department of Physics, Zanjan University, Zanjan, 45195-313, Iran; 4 Industrial Management Faculty, Tehran, Iran; 5 Center of Excellence in Electrochemistry, Faculty of Science, Faculty of Science, Tehran, Tehran, 14155-6455, Iran; 6 Faculty of Chemical Engineering, Oklahoma State University, Stillwater, Oklahoma, 74078 ; 7 Department of Chemistry, Sharif University of Technology, Tehran, Iran; 8 University of Lorraine, CNRS, IJL, Epinal, 88000, France; 9 Stanford Cardiovascular Research Institute, Stanford, California, USA; 10 Department of Medicine, Stanford University School of Medicine, California, USA *These authors made equal contributions to this work. Corresponding author: Ebrahim Mostafavi Stanford Cardiovascular Research Institute, Stanford University School of Medicine, Center of Excellence in Electrochemistry, School of Chemistry, Stamford Heran University, California, United States, Tehran, 14155-6455, Iran Email [Email is protected] Introduction: Nanotube-based drug delivery systems have received considerable attention for drugs and their ability to penetrate tissues, cells, and bacteria due to their large internal volume that can be encapsulated. In this regard, it is important to understand the interaction between the drug and the nanotube to evaluate the encapsulation behavior of the drug in the nanotube. Method: In this work, the encapsulation process of a cationic antimicrobial peptide named cRW3 in biocompatible boron nitride nanotubes (BNNT) was studied under the norm set (NVT) by molecular dynamics (MD) simulation. Result: The peptide was absorbed by BNNT through the van der Waals (vdW) interaction between cRW3 and BNNT. The vdW interaction was reduced during the simulation and reached a value of -142.7 kcal·mol-1 at 4 ns. Discussion: During the process of pulling cRW3 out of the nanotube, the increase in the potential average force distribution of the encapsulated peptide indicates that its insertion into the BNNT occurs spontaneously and that the inserted peptide has the required stability. During the encapsulation process, when half of the peptide is inside the BNNT, the energy barrier at the entrance of the BNNT will cause a pause of 0.45 ns. Therefore, during this period, the peptide experienced the weakest movement and the smallest conformational change. Keywords: Boron Nitride Nanotubes, Drug Delivery, Antimicrobial Peptides, Molecular Dynamics Simulation, Encapsulation

Since the advent of the first antibacterial drug penicillin in the 1960s, tremendous progress has been made in the treatment of infections1. However, even with the application of antimicrobial peptides, many obstacles have been encountered in curing microbial infections. 2 For example, pathogens are considered resistant to specific antibiotics, making scientific research unprofitable. 3 In this regard, the emergence of the field of antimicrobial drug delivery has paved the way for the treatment of infections. 4,5 Through the drug delivery system, maintain the benefits of delivery and overcome side effects in a targeted manner, 6-9 delay antimicrobial drug resistance, 10,11 and protect the drug from free radicals and enzyme oxidation and catalysis, respectively 12 ,13.

Nanoparticle-based antibacterial drug delivery systems consist of biocompatible and non-toxic nanoparticles with a hydrodynamic diameter of 10 to 100 nm, which contain encapsulated or attached antibacterial drugs. 14-17 These drug delivery nanosystems are generally divided into six main groups, including solid nanoparticles, polymer micelles, polymer nanoparticles, liposomes, viral nanoparticles, and dendrimers. 18-21 In addition to the advantages of the above-mentioned drug delivery system, nanocarriers will provide the benefits of a high response zone and ability to penetrate cells, tissues and bacteria. 22–25

As a fascinating nanocarrier, nanotubes have attracted a lot of attention as drug carriers due to their unique characteristics, such as having a large enough internal volume for drug encapsulation26 and surface functionalization. 27-29 In recent decades, carbon nanotubes (CNT) have been widely used 30 However, the possible cytotoxicity of carbon nanotubes limits their use in biomedical applications. 30,31 Therefore, Boron Nitride Nanotubes (BNNT) are non-toxic and biocompatible due to their structural stability, so they have been introduced as alternatives. Polarization shows a higher water permeability coefficient. 37

In this regard, several types of studies have been conducted to study the performance of BNNT as a drug carrier. For example, Mortazavifar et al.38 have used density functional theory (DFT) calculations and molecular dynamics (MD) simulations to verify the drug delivery performance of OH-functionalized BNNT. According to the adsorption energy calculated by DFT, it is observed that the anti-cancer drug Carmustine (CMT) binds to the surface of BNNT through hydrogen bonds with the hydroxyl groups on the surface of the nanotubes. In addition, they reported that increasing CMT concentration and temperature resulted in higher van der Waals forces between OH-functionalized BNNT and drug molecules. In another work by Roosta et al. 39, MD simulations were used to study the encapsulation of gemcitabine in BNNT (18, 0) and the drug release performance of the release agent using isofullerene (C48B12). Regarding encapsulation, since the negative interaction energy value is -0.9 kcal mol-1, the drug is located spontaneously in the center of the BNNT over its entire length. Regarding the release of the encapsulated drug, the C48B12 release agent was added to the system and entered the BNNT, resulting in the release of the drug, with a total potential energy difference of -140.1 kcal mol-1.

There are important works in the literature on the potential biomedical applications of BNNT using different solvents. Mirhaji et al40 used MD simulations to verify the effect of solvents containing water and ethanol on the encapsulation process of the anticancer drug docetaxel in BNNT (13, 13). According to calculated van der Waals energy, solutions containing 60% and 75% ethanol have a negative effect on the interaction between docetaxel and BNNT. The study by Khatti et al. compared the permeability of carboplatin drugs in BNNT and BNNT with 18 hydroxyl groups on one side. 41 It was observed that the hydroxyl group facilitated the entry of the drug into the nanotube lumen. Xu et al42 compared the adsorption process of two anticancer drugs temozolomide (TMZ) and CMT in the presence of BNNT (6, 6) as a nanocarrier through DFT calculation. They reported that the drug adsorption energy on the inner wall of BNNT was significantly higher than that on the outer wall. In addition, TMZ is adsorbed on the surface of the nanotubes through π-π and electrostatic interactions, which results in higher adsorption energy than the CMT/BNNT system with only electrostatic interactions.

MD simulation is considered to be a promising tool for predicting the performance of systems containing nanostructures in various fields. 43,44 In addition to evaluating the mechanical and thermal properties of nanomaterials, the calculation method 45-53 also provides the ability to evaluate the interaction between atoms. Complex nanoparticle-based system with biomolecules. 54 Therefore, in the current work, this method has been applied to study the atomic interaction and conformational changes in the process of peptide insertion into BNNT. According to previous studies on drug encapsulation in BNNT, the interaction between nanotubes and drugs is a key parameter in the encapsulation process. The drug should indeed pass through the barrier at the entrance of the nanotube, and then stabilize to the deep internal potential through the encapsulation process. Therefore, in order to evaluate the performance of BNNT as a nanocarrier, it is very important to calculate the Van der Waals interaction between the drug and the nanotube during the encapsulation process and the potential of the average force (PMF) of the encapsulated drug. In this way, the selected drug cRW3 is a small cationic antimicrobial peptide, which has a cyclic structure in BNNT and acts as a nanocarrier for drug delivery in an aqueous environment. This effect has been verified by using MD simulation. Subsequently, the encapsulation of the drug in BNNT was evaluated by estimating the van der Waals interaction between the drug and BNNT. In addition, the stability of the drug in BNNT was studied by calculating the PMF of the encapsulated drug.

In the current work, the large-scale atomic/molecular simulator (LAMMPS) software is used to apply MD calculations to verify the encapsulation process of the drug cRW3 in boron nitride nanotubes (BNNT), and the subsequent stability of the encapsulated drug in the nanotubes . The visualization is obtained using VMD. 56 According to the size of cRW3, the armchair BNNT (12,12) with a length of 30  was selected as the drug nanocarrier. The axial direction of the nanotube is taken as the z-axis considered by the simulation box. The drug cRW3 is selected from the protein database (ID code 2OTQ). The chemical structure of cRW3 (cyclo-(Arg-Arg-Trp-Phe-Trp-Arg)) is shown in Figure 1. The aromatic group (tryptophan side chain) is responsible for the hydrophobic character, while the arginine group is responsible for the hydrophilic part of cRW3.57,58. Figure 1 Amino acids based on the chemical structure of the drug cRW3.

Figure 1 Amino acids based on the chemical structure of drug cRW3.

At the beginning of the simulation, cRW3 was placed at an initial distance of 2  from BNNT. The complex of BNNT and cRW3 was immersed in a simulation box composed of TIP3P water molecules with periodic boundary conditions. Then the counter ion is introduced into the simulation box to neutralize the simulation solution. The Tersoff potential is used to study the interaction between boron and nitrogen. 59 All MD simulations are performed using the CHARMM27 force field. 60 In order to verify the drug packaging process, first, the system was minimized in the 300 K NVT set, and the BNNT was repaired. Secondly, MD runs in NPT integration for 4 ns with a time step of 1 fs. For the vdW interaction, the inner and outer cut-off distances of the Lennard-Jones and Coulomb potentials are 8 and 12 , respectively. The Lorentz-Berthelot combination rule is used to estimate the Lennard-Jones potential parameters of the vdW interaction between non-bonded atoms. 61 The vdW interaction between cRW3 and BNNT can be obtained: 56 (1)

Among them is the vdW interaction between cRW3 and BNNT, which corresponds to the vdW interaction between cRW3 and BNNT, and refers to the vdW energy of cRW3 and BNNT, respectively.

Regarding the stability of the drug encapsulated in BNNT, an external force is applied to the encapsulated cRW3 along the z-axis of the nanotube to pull it out of the BNNT in the direction opposite to the penetration process. The traction speed and spring constant k are 0.005  ps-1 and 15 kcal mol-1 -2, respectively. 62 According to the Jarzynski equation, the traction process is repeated ten times to obtain the potential of the mean force (PMF) distribution: 60 (2)

Where ΔG and W represent the free energy difference between the two states and the work done to the system, respectively. β is equal to (T)-1, which refers to Boltzmann's constant.

Langevin kinetics is believed to ensure 300 K as the simulated temperature. The Langevin piston Nose'-Hoover method is also used to fix the atmospheric pressure.

The package of BNNT (12,12) by cRW3 is monitored by MD simulation. The snapshots taken by VMD software at different times are shown in Figure 2. It can be seen that cRW3 was successfully inserted into the nanotube and remained stable to 4 ns. Figure 3A shows the normalized centroid (CoM) distance between the peptide and BNNT, d/d0, where d0 is equal to 23.43 Å as a function of simulation time. The fluctuation and decrease of the d/d0 value at the beginning of the simulation confirmed that the peptide was automatically adjusted during the BNNT entry. After the peptide completely entered the nanotube lumen at 0.9 ns, the CoM distance between the peptide and BNNT remained roughly stable until 4 ns at the end of the simulation. Figure 2 Representative snapshots of inserting cationic antimicrobial peptide cRW3 into armchair (12,12) BNNT at different times. For clarity, water molecules are not shown. Figure 3 (A) d/d0 (normalized CoM distance, where d0 is the initial CoM distance) between cationic antimicrobial peptide cRW3 and boron nitride nanotubes as a function of simulated time; (B) cRW3 and BNNT (12, 12) The vdW interaction between as a function of simulation time. The yellow area indicates the packaging period.

Figure 2 Representative snapshots of inserting cationic antimicrobial peptide cRW3 into armchair (12,12) BNNT at different times. For clarity, water molecules are not shown.

Figure 3 (A) d/d0 (normalized CoM distance, where d0 is the initial CoM distance) between cationic antimicrobial peptide cRW3 and boron nitride nanotubes as a function of simulated time; (B) cRW3 and BNNT (12, 12) The vdW interaction between as a function of simulation time. The yellow area indicates the packaging period.

Due to the neutralizing nature of BNNT, the value of Coulomb interactions (including hydrogen bonds and dipole-dipole interactions) between BNNT and peptides is zero. Therefore, the vdW interaction energy (such as the π-π interaction between the aromatic ring of the peptide and the BNNT) is considered to be the absorption energy of the peptide into the BNNT cavity.

In order to determine the effect of the vdW interaction energy between the peptide and BNNT during the encapsulation process, the variation of the cRW3-BNNT vdW interaction energy with the simulation time was estimated, and the results were plotted as the curve shown in Figure 3B. As expected, during the encapsulation process, the vdW interaction energy of the cRW3-BNNT complex decreases as the d/d0 value decreases, and reaches -142.7 kcal·mol-1 after the peptide is fully inserted into the nanotube cavity. value. Time of 4 ns. Huajian et al. 63 and Kang et al. 64 respectively reported that the vdW energy of DNA oligonucleotides and collagen-like peptides spontaneously inserted into CNTs showed a downward trend. In another study conducted by Malki et al.,65 the vdW and electrostatic interaction between doxorubicin (DOX) and CNT were studied. They proved that, due to the zero value of electrostatic interaction, the absorbance of DOX on CNT is due to the vdW interaction which has a favorable negative value.

When half of the peptide enters BNNT, the vdW interaction energy drops rapidly until 0.34 ns. Then, for 0.45 ns, the peptide did not move in the nanotube and remained approximately static (the CoM distance did not decrease), and the peptide-BNNT vdW interaction energy did not change significantly. It can be explained that this phenomenon is related to the period when the peptide passes the maximum barrier energy at the entrance of BNNT when half of the peptide is inserted into the lumen of the nanotube. 62 The yellow area in Figure 3 illustrates the packaging process during this period. After passing through this energy barrier, the peptide is quickly absorbed into the nanotube.

After fully inserting cRW3 into the BNNT in 4 ns, it was pulled out by MD simulation at a speed of 0.005  ps-1 to obtain the PMF curve of the encapsulated peptide, and the process was selected according to the encapsulation speed. The simulation is repeated ten times to calculate the average work (W) for each pulling distance, which is represented as a PMF curve in Figure 4. In addition, the peptide position of BNNT corresponding to the z-axis is also explained. It is observed that the free energy of the simulated system increases during the drawing process, reaching a value of 89.7 kcal·mol-1 when the drawing distance is 34 Å. This is very consistent with the way that the encapsulation process occurs spontaneously with a free energy of -89.7 kcal·mol-1. This observation is very consistent with the results obtained in the work done by Veclani et al. Therefore, the free energy of the adsorption process of ciprofloxacin on the CNT surface is negative (ΔG=-9.5 kcal·mol-1). Figure 4 The average force (PMF) potential calculated from 10 pulls by MD simulation. The image represents the position of the cationic antimicrobial peptide cRW3, corresponding to the z coordinate of a key position along the BNNT.

Figure 4 The average force (PMF) potential calculated from 10 pulls by MD simulation. The image represents the position of the cationic antimicrobial peptide cRW3, corresponding to the z coordinate of a key position along the BNNT.

When half of the peptide enters the BNNT, a small barrier energy is detected in the PMF curve of the cRW3-BNNT system, which is an enthalpy phenomenon. According to reports, during the insertion of water molecules, there is a similar resistance corresponding to the potential energy barrier at the entrance of the carbon nanotubes. 67 explained that due to the vdW interaction, the peptide is absorbed into the BNNT cavity, which overcomes the hydrogen bond between water molecules. By reducing the distance between BNNT and cRW3, the accumulation of hydrogen bond networks near and within BNNT caused a 0.45 ns pause during the encapsulation process. However, the cRTW3-BNNT vdW interaction disrupts these hydrogen bond networks and overcomes the energy barrier, which makes the peptides within the nanotubes have a favorable encapsulation process. 62

Figure 5A depicts the change of peptide structure at 0 and 4 ns in MD simulation. The left panel of Figure 5A is due to the peptide immersed in water molecules in its natural form at 0 ns. The figure on the right represents the conformation of the peptide adjusted to the BNNT structure at 4 ns, indicating that the conformation of the peptide has adapted to the geometry of the BNNT after it is fully inserted into the nanotube lumen. Zhang et al. reported that the configuration and arrangement of DOX encapsulated in single-walled carbon nanotubes have similar changes according to the diameter and chirality of the nanotubes. 68 Figure 5 (A) 0 ns and 4 ns of cationic antimicrobial peptide cRW3 in MD simulation. For clarity, water molecules are not shown. (B) The root mean square deviation (RMSD) of cRW3 as a function of simulation time. (C) The radius of gyration of cRW3 as a function of simulation time. The yellow area indicates the packaging period.

Figure 5 (A) Axial view of cationic antimicrobial peptide cRW3 at 0 ns and 4 ns in MD simulation. For clarity, water molecules are not shown. (B) The root mean square deviation (RMSD) of cRW3 as a function of simulation time. (C) The radius of gyration of cRW3 as a function of simulation time. The yellow area indicates the packaging period.

Figure 5B shows the root mean square deviation (RMSD), which reveals changes in peptide conformation as a function of simulated time. As shown in the figure, the RMSD has a significant change of 0.34 ns, indicating that the change in peptide conformation is affected by the high cRW3-BNNT vdW interaction. The yellow area corresponds to the time for half of the peptide to be inserted into the BNNT, and the encapsulation process is interrupted by 0.45 ns. It was observed that during this period, not only did the peptide not move to BNNT, but also the configuration of the peptide did not change significantly due to the energy barrier near BNNT. However, since then, the RMSD fluctuated within the specified range, which indicates that the peptide self-adjusted the internal geometry of BNNT. In addition, due to the small size and cyclic structure of the peptide, all hydrophobic and hydrophilic parts are equally affected by the hydrophilic solvent and hydrophobic nanotubes, so no significant phase separation between the hydrophobic and hydrophilic groups is observed. However, in systems containing larger biomolecules (such as proteins), different affinities of hydrophobic and hydrophilic groups for solvents and nanotubes can be observed. 69

Taking into account the change in the radius of gyration of the peptide during the encapsulation process (Figure 5C), it was observed that the peptide was stretched by the cRTW3-BNNT vdW interaction until the simulation time was 0.34 ns, which resulted in a peptide with an increased radius of gyration. Then, within a time period of 0.45 s (half of the peptides are in the yellow area of ​​BNNT), the radius of gyration reaches its minimum value, showing that the size of the peptide changes during this period to match the adjustment process towards the BNNT. The entrance of BNNT hole. Subsequently, the configuration of the peptide becomes a more stable state, with a higher radius of rotation, about 6.1 Å. Figure 6A shows the change in the distance between the central axis of BNNT and the CoM of peptide cRW3 during the simulation. At 0 ns, the peptide is located at the designated position in the simulation box to adjust the CoM of the peptide on the central axis of BNNT. The peptide is then transferred to one side of the BNNT wall through vdW interaction, which correlates with the initial reorientation of the peptide, so that the cRW3 axis distance increases to 2.6 Å at 0.11 ns. However, the conformation of this peptide is also changed due to adsorption to the other sidewalls of BNNT, which may result in a decrease in the cRW3 axis distance. In other words, the hydrophobic group in the peptide structure is strongly affected by the vdW interaction between BNNT and the peptide, so that the CoM position of the peptide alternately changes toward the sidewall of the nanotube, which is represented by the cRW3 axis distance curve during the encapsulation process. . Figure 6 (A) the distance between the CoM of cRW3 and the central axis of BNNT; (B) the potential energy of cRW3 as a function of simulation time, both of which are functions of simulation time. The yellow area indicates the packaging period.

Figure 6 (A) the distance between the CoM of cRW3 and the central axis of BNNT; (B) the potential energy of cRW3 as a function of simulation time, both of which are functions of simulation time. The yellow area indicates the packaging period.

Figures 6A and B illustrate the potential energy change of cRW3 during the simulation. It can be seen that at the beginning of the encapsulation process, the potential energy of cRW3 increases undesirably, corresponding to a low stability conformation. When half of the peptides are placed in the BBNT cavity and the encapsulation process is paused (yellow area in Figure 6B), the potential energy of the peptide reaches its minimum value, which is beneficial to continue the insertion process after this pause in the encapsulation process. The reduction of the peptide's potential energy is compensated by the system's energy due to the adjustment of the peptide's conformation. Since then, the cRTW3-BNNT vdW interaction overcomes the energy barrier, and the potential energy of the peptide increases again. As described above, the fluctuation of the potential energy of the peptide fully inserted into the BNNT is attributed to the continuous change in conformation.

In order to have a deeper understanding of the conformational changes (self-adjustment) of the peptide during the encapsulation process, especially during the time period when the peptide enters the BNNT cavity, the distance of each residue in the peptide cRTW3 structure is calculated from the central axis of the BNNT. It can be seen from Figure 7 that at the beginning of the simulation, the distance between the residue and the central axis of BNNT varies greatly, corresponding to the freedom of movement of the peptide structure in its natural state. However, by bringing the peptide closer to the cavity of the BNNT, these changes became smoother. At the end of the yellow area, half of the peptide was inserted into the BNNT. Until the end of the simulation, all distances fluctuated in the narrow area. These observations confirmed the stability of the encapsulated peptide under the influence of the vdW interaction energy between the peptide residues and the inner wall of BNNT. Figure 7 The distance between the residues in the cRW3 structure of the drug and the central axis of BNNT (20, 20). The yellow area indicates the packaging period.

Figure 7 The distance between the residues in the cRW3 structure of the drug and the central axis of BNNT (20, 20). The yellow area indicates the packaging period.

In other words, the conformational changes of the peptide residues in the yellow region make a great contribution to the encapsulation process, so the peptide can pass the energy barrier near BNNT. During this period: 1) the peptide did not move in the direction of the BNNT cavity, 2) the vdW energy between the BNNT and the peptide did not decrease, 3) the potential energy of the peptide decreased, which was conducive to the insertion process, 4) the radius of gyration of the peptide reached the minimum, 5 ) The change in RMSD is not significant. At the end of this period, the peptide was appropriately adjusted to the minimum value of potential and vdW energy related to the geometry of the BNNT inner wall, which confirmed the stability of the encapsulated peptide.

In the current work, the encapsulation process of the antimicrobial peptide cRW3 in boron nitride nanotubes (BNNT) in an aqueous medium was explored by MD simulation. It was observed that the peptide-BNNT vdW interaction energy and the normalized centroid (CoM) distance d/d0 between the peptide and BNNT decreased during the encapsulation process and reached values ​​of -142.7 kcal·mol-1 and 0, respectively. The calculation of the potential average force through the stretching process shows that the encapsulation process occurs spontaneously, and the free energy is -89.7 kcal·mol-1. In 0.45 ns, when half of the peptides were inserted into the BNNT cavity, the encapsulation process was interrupted due to the energy barrier caused by the hydrogen bond network accumulated near the nanotubes. During this period, it was found that: d/d0 and the vdW interaction energy between the peptide and BNNT did not change significantly. According to the root mean square deviation of the peptide and the change in the radius of gyration, the latter has no significant conformational change and the radius of gyration is the smallest. The reduction of peptide potential energy occurs due to the conformational adjustment of the peptide.

BNNT has promising properties such as large internal volume, ability to penetrate tissues, biocompatibility, chemical inertness, non-toxicity and acceptable water solubility, which makes it a new nanocarrier based on drug therapy. In addition, according to the obtained results, it was proved that the cationic antimicrobial peptide cRW3 was successfully encapsulated into BNNT spontaneously through the required vdW interaction between the peptide and BNNT. Due to the above factors, BNNT-based drug delivery systems can be considered as an effective method to delay antimicrobial resistance. Therefore, it is necessary to further study the performance of BNNT theoretically and experimentally in order to make significant progress in the field of nanomedicine.

All data reported here can be provided at the request of the corresponding author.

The authors report no conflicts of interest in this work.

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