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1.
Proc Natl Acad Sci U S A ; 106(17): 6933-8, 2009 Apr 28.
Article in English | MEDLINE | ID: mdl-19369210

ABSTRACT

The recent characterization of the prokaryotic Cys(2)His(2) zinc-finger domain, identified in Ros protein from Agrobacterium tumefaciens, has demonstrated that, although possessing a similar zinc coordination sphere, this domain is structurally very different from its eukaryotic counterpart. A search in the databases has identified approximately 300 homologues with a high sequence identity to the Ros protein, including the amino acids that form the extensive hydrophobic core in Ros. Surprisingly, the Cys(2)His(2) zinc coordination sphere is generally poorly conserved in the Ros homologues, raising the question of whether the zinc ion is always preserved in these proteins. Here, we present a functional and structural study of a point mutant of Ros protein, Ros(56-142)C82D, in which the second coordinating cysteine is replaced by an aspartate, 5 previously-uncharacterized representative Ros homologues from Mesorhizobium loti, and 2 mutants of the homologues. Our results indicate that the prokaryotic zinc-finger domain, which in Ros protein tetrahedrally coordinates Zn(II) through the typical Cys(2)His(2) coordination, in Ros homologues can either exploit a CysAspHis(2) coordination sphere, previously never described in DNA binding zinc finger domains to our knowledge, or lose the metal, while still preserving the DNA-binding activity. We demonstrate that this class of prokaryotic zinc-finger domains is structurally very adaptable, and surprisingly single mutations can transform a zinc-binding domain into a nonzinc-binding domain and vice versa, without affecting the DNA-binding ability. In light of our findings an evolutionary link between the prokaryotic and eukaryotic zinc-finger domains, based on bacteria-to-eukaryota horizontal gene transfer, is discussed.


Subject(s)
Bacterial Proteins/chemistry , Bacterial Proteins/metabolism , Zinc Fingers , Zinc/chemistry , Zinc/metabolism , Alphaproteobacteria/chemistry , Alphaproteobacteria/genetics , Alphaproteobacteria/metabolism , Amino Acid Sequence , Bacterial Proteins/genetics , Cations , Hydrophobic and Hydrophilic Interactions , Mass Spectrometry , Molecular Sequence Data , Nuclear Magnetic Resonance, Biomolecular , Protein Binding , Protein Structure, Secondary , Sequence Alignment , Sequence Homology, Amino Acid
2.
Int J Mol Sci ; 9(3): 299-315, 2008 Mar.
Article in English | MEDLINE | ID: mdl-19325750

ABSTRACT

The discovery of siRNAs as the mediators of RNA interference has led to an increasing interest in their therapeutic applications. Chemical modifications are introduced into siRNAs to optimize the potency, the stability and the pharmacokinetic properties in vivo. Here, we synthesize and test the effects of RNA-3'-PNA chimeras on siRNA functioning and stability. We demonstrate that the chemical modifications are compatible with the siRNA machinery, because all the PNA-modified siRNAs can efficiently mediate specific gene silencing in mammalian cells. Furthermore, we find that the modification on the sense strand of siRNA results in an increased persistence of the activity, whereas modification on both strands results in enhanced nuclease resistance in serum.

3.
Proc Natl Acad Sci U S A ; 104(44): 17341-6, 2007 Oct 30.
Article in English | MEDLINE | ID: mdl-17956987

ABSTRACT

The first putative prokaryotic Cys(2)His(2) zinc-finger domain has been identified in the transcriptional regulator Ros from Agrobacterium tumefaciens, indicating that the Cys(2)His(2) zinc-finger domain, originally thought to be confined to the eukaryotic kingdom, could be widespread throughout the living kingdom from eukaryotic, both animal and plant, to prokaryotic. In this article we report the NMR solution structure of Ros DNA-binding domain (Ros87), providing 79 structural characterization of a prokaryotic Cys(2)His(2) zinc-finger domain. The NMR structure of Ros87 shows that the putative prokaryotic Cys(2)His(2) zinc-finger sequence is indeed part of a significantly larger zinc-binding globular domain that possesses a novel protein fold very different from the classical fold reported for the eukaryotic classical zinc-finger. The Ros87 globular domain consists of 58 aa (residues 9-66), is arranged in a betabetabetaalphaalpha topology, and is stabilized by an extensive 15-residue hydrophobic core. A backbone dynamics study of Ros87, based on (15)N R(1), (15)N R(2), and heteronuclear (15)N-{(1)H}-NOE measurements, has further confirmed that the globular domain is uniformly rigid and flanked by two flexible tails. Mapping of the amino acids necessary for the DNA binding onto Ros87 structure reveals the protein surface involved in the DNA recognition mechanism of this new zinc-binding protein domain.


Subject(s)
Agrobacterium tumefaciens/chemistry , Bacterial Proteins/chemistry , DNA-Binding Proteins/chemistry , DNA/chemistry , DNA/metabolism , Protein Folding , Repressor Proteins/chemistry , Zinc Fingers , Agrobacterium tumefaciens/genetics , Amino Acid Sequence , Bacterial Proteins/genetics , Bacterial Proteins/metabolism , Binding Sites , Cysteine/genetics , Cysteine/metabolism , DNA-Binding Proteins/genetics , DNA-Binding Proteins/metabolism , Histidine/genetics , Histidine/metabolism , Hydrophobic and Hydrophilic Interactions , Models, Molecular , Molecular Sequence Data , Nuclear Magnetic Resonance, Biomolecular , Protein Structure, Tertiary , Repressor Proteins/genetics , Repressor Proteins/metabolism , Sequence Alignment
4.
Biopolymers ; 88(6): 815-22, 2007.
Article in English | MEDLINE | ID: mdl-17918186

ABSTRACT

Peptide nucleic acids (PNAs) are oligonucleotide mimics in which the sugar-phosphate backbone has been replaced by a pseudo-peptide backbone. Among PNA-based molecules, PNA-DNA conjugates characterized by tracts of DNA bound to N and/or C terminus of PNA are very soluble in aqueous media, are able to recognize exclusively single strands of DNA and RNA in antiparallel fashion, activate RNAse H, bind to transcription factors and are more stable than DNA to nucleases degradation. Very little information is available on chimeras constituted of alternating monomers of PNA and DNA. In this article, we describe a simple fully automated strategy for the synthesis of 6-mer and 10-mer alternate PNA-DNA chimeras consisting of polythymine oligomers, stability assays in fetal calf serum, UV and CD studies of the single strand alternate chimeras and of alternate chimera/DNA and alternate chimera/RNA duplexes. Evidences supporting the formation of duplex hybrids were found. Furthermore, the ability of forming Hoogsteen base pairing with duplex DNA was investigated. Finally, we tested the ability of the PNA-DNA alternates in (a) interfering with reverse transcription of eukaryotic mRNA and (b) inhibiting DNA-protein interactions.


Subject(s)
DNA/chemistry , Peptide Nucleic Acids/chemistry , Animals , Base Pairing/drug effects , Binding Sites , Cattle , Chromatography, High Pressure Liquid/methods , Circular Dichroism/methods , DNA/antagonists & inhibitors , Electrophoretic Mobility Shift Assay/methods , Eukaryotic Cells/chemistry , Fetal Blood/chemistry , Humans , Molecular Structure , Peptide Nucleic Acids/chemical synthesis , Peptide Nucleic Acids/pharmacology , Proteins/antagonists & inhibitors , RNA/chemistry , RNA, Messenger/chemistry , RNA, Messenger/genetics , Reverse Transcriptase Polymerase Chain Reaction/methods , Spectrophotometry, Ultraviolet/methods , Thymine/chemistry , Time Factors , Transcription, Genetic/drug effects
5.
J Inorg Biochem ; 101(2): 254-60, 2007 Feb.
Article in English | MEDLINE | ID: mdl-17097738

ABSTRACT

Oxidative addition reactions between [M(PPh(3))(4)] (M=Pt and Pd) and N1-methylthymine (t)/3',5'-di-O-acetylthymidine (T) were carried out to give [M(II)(PPh(3))(2)Cl t (or T)] complexes, in which the metal is coordinated to the N3 of the base. All complexes were characterized by spectroscopic analyses (IR, NMR) and Fast Atom Bombardment mass spectrometry (FAB-MS); X-ray data for the thymine complexes and elemental analysis for the thymidine complexes are reported. The antiproliferative activity of the complexes was tested on human chronic myelogenous leukaemia K562 cells. Arrested polymerase-chain reaction analysis was carried on to correlate antiproliferative activity and inhibition of DNA replication. All Pd and Pt complexes exhibit antiproliferative activity, Pd complexes resulting always more active than Pt complexes. Arrested PCR data are strongly in agreement with the effects on cell growth, suggesting that inhibition of the DNA replication by the synthesized compounds is the major basis for their in vitro antiproliferative activity.


Subject(s)
Cell Proliferation/drug effects , Palladium/chemistry , Palladium/pharmacology , Phosphines/chemistry , Phosphines/pharmacology , Platinum/chemistry , Platinum/pharmacology , Base Sequence , Crystallography, X-Ray , DNA Primers/genetics , Humans , K562 Cells , Phosphines/chemical synthesis , Thymidine/chemistry , Thymine/chemistry
6.
Bioorg Med Chem Lett ; 16(23): 6096-101, 2006 Dec 01.
Article in English | MEDLINE | ID: mdl-16971124

ABSTRACT

A novel antioxidant prenylated stilbenoid, distachyasin, has been isolated from the leaves of Carex distachya. Its structure has been elucidated on the basis of the spectroscopic characteristics. Bidimensional NMR, and crystallographic data and computational calculations have furnished important data useful for the characterization and the stereochemistry of the molecule. The compound has a tetracyclic skeleton derived from carexane. The compound has been assayed, for the antioxidant activity, by measuring its capacity to scavenge the H(2)O(2), nitric oxide, superoxide radical and to inhibit formation of TBARS (thiobarbituric acid reactive species).


Subject(s)
Antioxidants/chemistry , Antioxidants/metabolism , Carex Plant/chemistry , Carex Plant/metabolism , Polycyclic Compounds/chemistry , Polycyclic Compounds/metabolism , Stilbenes/chemistry , Stilbenes/metabolism , Free Radicals/chemistry , Hydrogen Peroxide/chemistry , Magnetic Resonance Spectroscopy , Models, Molecular , Molecular Structure , Nitrites/chemistry , Plant Leaves/chemistry , Plant Leaves/metabolism , Superoxides/chemistry , Thiobarbituric Acid Reactive Substances/chemistry , X-Ray Diffraction
7.
Biochemistry ; 45(34): 10394-405, 2006 Aug 29.
Article in English | MEDLINE | ID: mdl-16922516

ABSTRACT

Transcriptional factors bearing a Cys(2)His(2) zinc finger were thought to be confined to eukaryotes, but recent studies have suggested their presence also in prokaryotes. In this paper, we report the first complete functional characterization of the DNA binding domain present in the putative Cys(2)His(2) zinc finger-containing prokaryotic transcriptional regulator Ros from Agrobacterium tumefaciens. We demonstrate that in the single zinc binding motif present in the Ros protein the metal ion is coordinated by two cysteines (Cys79 and Cys82) and two histidines (His92 and His97), separated by a shorter spacer with respect to the eukaryotic classical Cys(2)His(2) domains. The Cys(2)His(2) zinc finger motif is essential for Ros DNA binding and is part of a larger DNA binding domain which includes four basic regions located on either side of the finger, one at the N-terminus and three at the C-terminus. The one described here is a novel type of DNA binding domain containing a noncanonical Cys(2)His(2) zinc finger motif which, by sequence alignment, seems to be conserved in all the bacterial putative zinc finger proteins identified so far. Interestingly, basic amino acids have been shown to be important in stabilizing the DNA binding of eukaryotic single Cys(2)His(2) zinc finger domains, confirming that the modality of DNA binding using a single zinc finger motif flanked by basic residues is widespread throughout the living kingdom from eukaryotic, both animal and plant, to prokaryotic, even if in each kingdom it presents its peculiarity.


Subject(s)
Agrobacterium tumefaciens/metabolism , Bacterial Proteins/metabolism , DNA, Bacterial/metabolism , DNA-Binding Proteins/metabolism , Repressor Proteins/metabolism , Agrobacterium tumefaciens/genetics , Amino Acid Sequence , Animals , Bacterial Proteins/genetics , DNA, Bacterial/genetics , DNA-Binding Proteins/genetics , Humans , Molecular Sequence Data , Plants/genetics , Plants/metabolism , Protein Binding/physiology , Protein Structure, Tertiary/genetics , Repressor Proteins/genetics , Sequence Alignment , Zinc/metabolism , Zinc Fingers/genetics
8.
Org Lett ; 8(10): 2015-8, 2006 May 11.
Article in English | MEDLINE | ID: mdl-16671770

ABSTRACT

[structure: see text] A new and versatile on-line automated solid-phase approach to obtain cyclic PNA (I and III) and cyclic PNA-DNA chimeras (II) in highly pure form has been developed. Starting from a Tentagel matrix functionalized with a 3-chloro-4-hydroxyphenylacetic linker, the synthesis of representative, new cyclic molecules by standard peptide and phosphoramidite-based chemistry has been achieved.


Subject(s)
DNA/chemical synthesis , Peptide Nucleic Acids/chemical synthesis , Cyclization , DNA/chemistry , Molecular Structure , Peptide Nucleic Acids/chemistry
9.
Biochemistry ; 43(20): 6043-58, 2004 May 25.
Article in English | MEDLINE | ID: mdl-15147188

ABSTRACT

No general strategy for thermostability has been yet established, because the extra stability of thermophiles appears to be the sum of different cumulative stabilizing interactions. In addition, the increase of conformational rigidity observed in many thermophilic proteins, which in some cases disappears when mesophilic and thermophilic proteins are compared at their respective physiological temperatures, suggests that evolutionary adaptation tends to maintain corresponding states with respect to conformational flexibility. In this study, we accomplished a structural analysis of the K18G/R82E Alicyclobacillus acidocaldarius thioredoxin (BacTrx) mutant, which has reduced heat resistance with respect to the thermostable wild-type. Furthermore, we have also achieved a detailed study, carried out at 25, 45, and 65 degrees C, of the backbone dynamics of both the BacTrx and its K18G/R82E mutant. Our findings clearly indicate that the insertion of the two mutations causes a loss of energetically favorable long-range interactions and renders the secondary structure elements of the double mutants more similar to those of the mesophilic Escherichia coli thioredoxin. Moreover, protein dynamics analysis shows that at room temperature the BacTrx, as well as the double mutant, are globally as rigid as the mesophilic thioredoxins; differently, at 65 degrees C, which is in the optimal growth temperature range of A. acidocaldarius, the wild-type retains its rigidity while the double mutant is characterized by a large increase of the amplitude of the internal motions. Finally, our research interestingly shows that fast motions on the pico- to nanosecond time scale are not detrimental to protein stability and provide an entropic stabilization of the native state. This study further confirms that protein thermostability is reached through diverse stabilizing interactions, which have the key role to maintain the structural folding stable and functional at the working temperature.


Subject(s)
Bacterial Proteins/chemistry , Bacterial Proteins/genetics , Hot Temperature , Mutation , Protein Structure, Secondary , Thioredoxins/chemistry , Thioredoxins/genetics , Bacterial Proteins/metabolism , Enzyme Stability , Models, Molecular , Molecular Sequence Data , Nuclear Magnetic Resonance, Biomolecular , Thioredoxins/metabolism
10.
Org Biomol Chem ; 1(17): 3131-7, 2003 Sep 07.
Article in English | MEDLINE | ID: mdl-14518138

ABSTRACT

Three new resorcin[4]arene-capped porphyrins (3, 5 and 7) different in the porphyrin skeleton, in the linking arms and in the cavity dimensions, have been synthesised. Molecular modelling calculations explored the conformations and the cavity size of the three compounds and showed that their hydrophobic pockets can accommodate one molecule of water or methane (3 and 5), or benzene (7) without any distortion. Notably, the capped porphyrin 5 was able to inhibit the oxidation of Co(II) to Co(III), whereas compound 7 did it only partially.

11.
Chembiochem ; 4(2-3): 171-80, 2003 Mar 03.
Article in English | MEDLINE | ID: mdl-12616630

ABSTRACT

Zinc finger domains of the classical type represent the most abundant DNA binding domains in eukaryotic transcription factors. Plant proteins contain from one to four zinc finger domains, which are characterized by high conservation of the sequence QALGGH, shown to be critical for DNA-binding activity. The Arabidopsis thaliana SUPERMAN protein, which contains a single QALGGH zinc finger, is necessary for proper spatial development of reproductive floral tissues and has been shown to specifically bind to DNA. Here, we report the synthesis and UV and NMR spectroscopic structural characterization of a 37 amino acid SUPERMAN region complexed to a Zn(2+) ion (Zn-SUP37) and present the first high-resolution structure of a classical zinc finger domain from a plant protein. The NMR structure of the SUPERMAN zinc finger domain consists of a very well-defined betabetaalpha motif, typical of all other Cys(2)-His(2) zinc fingers structurally characterized. As a consequence, the highly conserved QALGGH sequence is located at the N terminus of the alpha helix. This region of the domain of animal zinc finger proteins consists of hypervariable residues that are responsible for recognizing the DNA bases. Therefore, we propose a peculiar DNA recognition code for the QALGGH zinc finger domain that includes all or some of the amino acid residues at positions -1, 2, and 3 (numbered relative to the N terminus of the helix) and possibly others at the C-terminal end of the recognition helix. This study further confirms that the zinc finger domain, though very simple, is an extremely versatile DNA binding motif.


Subject(s)
Amino Acid Sequence , Arabidopsis Proteins/chemistry , DNA-Binding Proteins/chemistry , Magnetic Resonance Spectroscopy/methods , Protein Conformation , Transcription Factors/chemical synthesis , Zinc Fingers/physiology , Amino Acids/analysis , Molecular Structure , Peptide Biosynthesis
12.
Chembiochem ; 4(1): 73-81, 2003 Jan 03.
Article in English | MEDLINE | ID: mdl-12512079

ABSTRACT

The conformational features of human melanin-concentrating hormone (hMCH) [Asp1-Phe2-Asp3-Met4-Leu5-Arg6-cyclo(S[bond]S)(Cys7-Met8-Leu9-Gly10-Arg11-Val12-Tyr13-Arg14-Pro15-Cys16)-Trp17-Gln18-Val19], in water and in a CD(3)CN/H(2)O (1:1 v/v) mixture at 298 K, have been determined by NMR spectroscopy followed by simulated annealing and molecular dynamics analyses to identify conformer populations. Backbone clustering analysis of NMR-spectroscopy-derived structures in the 7-16 peptide region led to the identification of a single representative structure in each solvent. Both root mean square deviation clustering and secondary structure analysis of the final conformers in both solvents show substantial convergence of most conformers into a single fold in the 4-17 region, with a limited variability around Gly10 and Tyr13 on going from CD(3)CN/H(2)O to pure water. The main feature deduced from the analysis of secondary structures is the occurrence of an N-terminal alpha helix of variable length, which spans an overall residue range of 2-9. A comparative analysis in the two solvents highlights that these structures are substantially different from that reported in the literature for the cyclic MCH(5-14) subunit of salmon MCH, which was used to perform a molecular characterization of the MCH/receptor complex. Our conformational data call for a critical revision of the proposed MCH/receptor complex model.


Subject(s)
Hypothalamic Hormones/chemistry , Melanins/chemistry , Pituitary Hormones/chemistry , Amino Acid Sequence , Circular Dichroism , Computational Biology , Humans , Hydrogen Bonding , Magnetic Resonance Spectroscopy , Models, Molecular , Molecular Sequence Data , Protein Conformation , Solvents
13.
Nucleic Acids Res ; 30(22): 4945-51, 2002 Nov 15.
Article in English | MEDLINE | ID: mdl-12433998

ABSTRACT

The Arabidopsis SUPERMAN (SUP) gene has been shown to be important in maintaining the boundary between stamens and carpels, and is presumed to act by regulating cell proliferation. In this work, we show that the SUP protein, which contains a single Cys2-His2 zinc finger domain including the QALGGH sequence, highly conserved in the plant zinc finger proteins, binds DNA. Using a series of deletion mutants, it was determined that the minimal domain required for specific DNA binding (residues 15-78) includes the single zinc finger and two basic regions located on either side of this motif. Furthermore, amino acid substitutions in the zinc finger or in the basic regions, including a mutation that knocks out the function of the SUP protein in vivo (glycine 63 to aspartate), have been found to abolish the activity of the SUP DNA-binding domain. These results strongly suggest that the SUP protein functions in vivo by acting as a DNA-binding protein, likely involved in transcriptional regulation. The association of both an N-terminal and a C-terminal basic region with a single Cys2-His2 zinc finger represents a novel DNA-binding motif suggesting that the mechanism of DNA recognition adopted by the SUP protein is different from that described so far in other zinc finger proteins.


Subject(s)
Arabidopsis Proteins/metabolism , DNA-Binding Proteins/chemistry , DNA-Binding Proteins/metabolism , Transcription Factors/chemistry , Transcription Factors/metabolism , Amino Acid Sequence , Amino Acids, Basic/physiology , Arabidopsis Proteins/chemistry , Arabidopsis Proteins/genetics , Binding Sites , Cysteine/metabolism , DNA/metabolism , DNA-Binding Proteins/genetics , Electrophoretic Mobility Shift Assay , Histidine/metabolism , Molecular Sequence Data , Sequence Deletion , Transcription Factors/genetics , Zinc Fingers
14.
Inorg Chem ; 35(15): 4497-4504, 1996 Jul 17.
Article in English | MEDLINE | ID: mdl-11666671

ABSTRACT

The ternary copper(II) complex of 6-deoxy-6-[(2-(4-imidazolyl)ethyl)amino]cyclomaltoheptaose (CDhm) and L-tryptophanate (L-TrpO(-)) was characterized by ESR and X-ray diffraction. The solid state structure of [Cu(CDhm)(L-TrpO)](+) shows that the aromatic side chain of TrpO(-) is outside the cavity and that the two amino nitrogen atoms, one from the histamine molecule and one from the amino acidate, are in a cis disposition. The two amino nitrogens, the imidazole nitrogen, and the carboxylate oxygen atoms form the base of a square pyramid, which surrounds the copper(II) ion, a water molecule occupying an apical position. Atomic distances suggest for this complex that pi-pi and d-pi interactions could occur in the solid state. Morover, the [Cu(CDhm)(L-TrpO)](+) has a self-assembled structure in which a CDhm molecule behaves as host and as guest. The imidazole and the indole ring are directed into the cavity of an adjacent CDhm molecule from the wider cyclodextrin rim, thus forming a polymeric column structure. ESR spectra were run on the copper(II) ternary complexes with L- or D-tryptophanate and L- or D-alaninate in frozen aqueous solution and on the former pair of enantiomers in the solid state, as well. While in the case of the ternary complex with L- or D-alaninate no differences are observed in their frozen solution spectra, in the case of complexes with TrpO(-) subtle differences are found. These differences, which disappear when excess methanol is used, are ascribed to the presence of weak forces, such as hydrophobic or d-pi interactions.

15.
Biopolymers ; 20(2): 283-302, 1981 Feb.
Article in English | MEDLINE | ID: mdl-33327685

ABSTRACT

The crystal structures of L-3,4-dehydroproline, t-butoxycarbonyl-L-3,4-dehydroproline amide, and acetyl-L-3,4-dehydroproline amide have been determined. L-3,4-Dehydroproline is orthorhombic with a = 16.756, b = 5.870, c = 5.275 Å, and Z = 4; t-butoxycarbonyl-L-3,4-dehydroproline amide is orthorhombic with a = 6.448, b = 8.602, c = 21.710 Å, and Z = 4; acetyl-L-3,4-dehydroproline amide is monoclinic with a = 4.788, b = 10.880, c = 7.785 Å, ß = 105.25°, and Z = 2. The final R value for the L-3,4-dehydroproline is 0.046 based on 529 reflections; for t-butoxycarbonyl-L-3,4-dehydroproline amide, 0.050 based on 792 reflections; and for acetyl-L-3,4-dehydroproline amide, 0.058 based on 632 reflections. The structures clearly establish that the free amino acid exists in the zwitterionic form in the crystalline state. The molecular conformations of the t-Boc and acetyl derivatives consist of two planes: one involving the primary amide and the other the remaining atoms of the molecule. The acetyl-L-3,4-dehydroproline amide contains a tertiary amide bond in the cis conformation. To the best of our knowledge, this is the first example of a cis bond in an acetyl derivative of an amino acid or peptide. At variance with the previously reported proline amides, which present ϕ and ψ values corresponding to those of a right-handed α-helical conformation (conformation A), the t-Boc and acetyl derivatives both have ϕ and ψ values corresponding to a collagenlike conformation (conformation F).

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