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J Biomol Tech. 2008 December; 19(5): 356–361.
PMCID: PMC2628075

Article Watch

This column highlights recently published articles that are of interest to the readership of this publication. We encourage ABRF members to forward information on articles they feel are important and useful to Clive Slaughter, Hartwell Center, St. Jude Children’s Research Hospital, 332 North Lauderdale St., Memphis TN 38105-2794. Tel: (901) 495-4844; Fax: (901) 495-2945; Email: gro.edujts@rethgualS.evilC or to any member of the editorial board. Article summaries reflect the reviewer’s opinions and not necessarily those of the Association.

MACROMOLECULAR SYNTHESIS

Yehezkel TB, Linshiz G, Buaron H, Kaplan S, Shabi U, Shapiro E. De novo DNA synthesis using single molecule PCR. Nucleic Acids Research 36;2008:e107.

This paper provides a scheme for removal of sequence errors during de novo synthesis of long DNA molecules from short, overlapping, unpurified, chemically synthesized oligonucleotides. Construction is recursive: segments of DNA are combined together in pairs, the products are subjected to error correction and are then used as templates for the next round of combinations. In vivo cloning is replaced by single-molecule PCR amplification for the sake of improved cost and throughput in choosing products with the best sequence fidelity for the next round. Single-molecule PCR is enabled by incorporating several procedural modifications, including the use of improved primer selection, calculation of the best dilution of DNA templates to ensure the optimal yield of products derived from single-template molecules, and stopping the PCR at the exponential phase of amplification to ensure that heterodimers are not formed. The products of this procedure are sequenced and error corrected by using error-free segments for amplification in the next round of single-molecule PCR.

Singla N, Himanen JP, Muir TW, Nikolov DB. Toward the semisynthesis of multidomain transmembrane receptors: Modification of Eph tyrosine kinases. Protein Science 17;2008:1740–1747.

The technique of expressed protein ligation has been used extensively for the synthesis or semisynthesis of intracellular proteins, and has enabled the introduction of chemical tags into the protein products. The procedure works by ligation together of peptides/proteins by reaction between an N-terminal cysteine residue on one polypeptide and a C-terminal thioester on the other polypeptide, created by reductive cleavage of a C-terminal intein (an autocatalytically processed protein) with which it is expressed. The use of the technique for the synthesis of transmembrane proteins is conceptually more difficult because the reducing conditions required for generating the C-terminal thioester might disrupt disulfide bridges that maintain the three-dimensional structure of extracellular domains. The present paper describes the successful use of expressed protein ligation for the addition of a transmembrane-like sequence to the C-termini of Eph tyrosine kinase extracellular domains. Conditions that maintain the activity of both the Eth domain and the intein are identified. This work opens the way to semisynthesis of membrane proteins with a single transmembrane segment for use in investigation of signaling mechanisms.

DNA CHARACTERIZATION AND GENOTYPING

Shendure J, Hanlee J. Next-generation DNA sequencing. Nature Biotechnology 26;2008:1135–1145.

This concise review compares the different platforms for cyclic-array (“next generation”) sequencing, including 454, Solexa, SOLiD, Polonator, and HeliScope. Their differing principles of operation are described, along with present read-length and accuracy statistics, and instrument prices and operational costs. The review also summarizes associated developments in software tools and progress in developing standards for data processing and guidelines for publication. This summary will be of interest to investigators seeking a general but rigorous orientation to trends in this rapidly evolving field.

Korn JM, Kuruvilla FG, McCarroll SA, Wysoker A, Nemesh J, Cawley S, Hubbell E, Veitch J, Collins PJ, Darvishi K, Lee C, Nizzari MM, Gabriel SB, Purcell S, Daly MJ, Altshuler D. Integrated genotype calling and association analysis of SNPs, common copy number polymorphisms and rare CNVs. Nature Genetics 40;2008:1253–1260.

Although genotyping for single nucleotide polymorphisms (SNPs) and copy number variants (CNVs) rely on somewhat different approaches and assumptions, these variants coexist in the genome and affect one another’s measurement. Here, computational methodology for integrating the analyses of SNPs and CNVs (both common and rare variants) is described. Firstly, copy number is assigned across regions of known CNVs. Secondly, genotypes are assigned for each SNP locus expected to have two copies. Thirdly, rare or previously unknown CNVs are discovered by using a hidden Markov model informed by values for probe-specific mean and variance derived from the second step. Finally, copy number and SNP information are combined to provide an integrated genotype at each locus, e.g., A-null, AAB, BBB, in addition to AA, AB, and BB. This results in a substantial reduction in the incidence of errors manifested as apparent inconsistencies with Mendelian inheritance or Hardy-Weinberg equilibrium, and enhances the accuracy of CNV catalogs used in association studies.

Pan X, Urban AE, Palejev D, Schulz V, Grubert F, Hu Y, Snyder M, Weissman SM. A procedure for highly specific, sensitive, and unbiased whole-genome amplification. Proceedings of the National Academy of Sciences, U.S.A. 105;2008:15499–15504.

In whole-genome amplification, multiple displacement methods, in which ϕ29 DNA polymerase and random exonuclease-resistant primers are used, and DNA is amplified at 30°C, give less allele and locus bias and higher sensitivity and efficiency than PCR-based methods. However, they generate template-independent product from oligonucleotides and exogenous DNA that can reach relatively high quantities when the amount of input DNA is small. The present paper describes modifications to the method that reduce template-independent product and further improve fidelity; specifically, the inclusion of trehalose at optimal concentration. The procedure eliminates background amplification in the absence of template, and produces essentially unbiased product from as little as 0.5–2.5 ng of genomic DNA (from a few cells). Known duplications and deletions are preserved, chromosome termini are well represented, and typing single nucleotide polymorphisms gave > 99.7% accuracy. The method is expected to facilitate the use of archived DNA samples, laser-dissected and needle-biopsy samples, and single or small numbers of cells for genomic analysis and expression profiling. Notably, the product is suitable for analysis of single nucleotide polymorphisms and copy number variants.

CARBOHYDRATE AND GLYCOPROTEIN ANALYSIS

Pabst M, Altmann F. Influence of electrosorption, solvent, temperature, and ion polarity on the performance of LC-ESI-MS using graphitic carbon for acidic oligosaccharides. Analytical Chemistry 80;2008:7534–7542.

Although superior selectivity characteristics for separation of oligosaccharides have been attributed to porous graphitic carbon (PGC), the use of this stationary phase for liquid chromatography in conjunction with electrospray ionization mass spectrometry has been relatively restricted. This paper examines the effects of PGC mobile phase composition on chromatographic separation and ionization efficiency for charged oligosaccharides to encourage more widespread use of the method. Firstly, polarization of the PGC column due to charging from the electrospray emitter downstream increases retention of monosialylated glycans and may prevent elution of multisialylated species. This problem can be eliminated by adequately grounding the column. Secondly, maintenance of adequate ionic strength is necessary to elute acidic (sulfated or sialylated) oligosaccharides, although reduction in electrospray ionization signal strength may be encountered. Thirdly, oligosaccharides of all types tested can be detected in both positive- and negative-ion modes, but detection sensitivity for acidic species is better in negative-ion mode. For purposes of quantification, the positive-ion mode is advantageous for the relatively uniform signal strength produced by both neutral and acidic glycans in the same sample.

METABOLOMICS AND SMALL MOLECULE ANALYSIS

Munger J, Bennett BD, Parikh A, Feng X-J, McArdle J, Rabitz HA, Shenk T, Rabinowitz JD. Systems-level metabolic flux profiling identifies fatty acid synthesis as a target for antiviral therapy. Nature Biotechnology 26;2008:1179–1186.

Measurement of metabolic flux in microbes is facilitated by the ability to feed labeled nutrients as part of minimal media. Mammalian cells, however, present a much more difficult task because of the complexity of their metabolism and of the culture media they require. In this paper, profiling of metabolic flux patterns is achieved by integrating measurements of metabolite influx and efflux from mammalian cells and specific steady-state metabolite labeling patterns quantified by LC-MS/MS after feeding the cells with 13C-glucose and 13C-glutamine. “Genetic algorithms” are used to search for flux combinations consistent with the experimental results. The method produces a large set of flux combinations that fit the data within 95% confidence limits. This approach avoids overfitting, and yields confidence limits for flux changes deduced. Changes in metabolic flux resulting from infection with human cytomegalovirus are evaluated in this way. Infection with the virus has previously been associated with large increases in the uptake of glucose and in the levels of intermediary metabolites involved in glycolysis, the tricarboxylic acid cycle and pyrimidine nucleotide biosynthesis. In addition to elevation of flux in nucleotide biosynthesis, the target of antimetabolites presently used to treat human cytomegalovirus infection, elevation of flux through the tricarboxylic acid cycle and its efflux to the fatty acid biosynthesis pathway detected here suggest that inhibitors of fatty acid biosynthesis (such as those developed for treating hyperlipidemia and obesity) may be useful in antiviral therapy. Treatment of cells with the acetyl-CoA carboxylase inhibitor, 5-tetradecyloxy-2-furoic acid are indeed found to reduce human cytomegalovirus replication > 1000× without toxicity to uninfected cells or induction of apoptosis. These results represent a significant expansion of the capabilities of metabolomics beyond the discovery of biomarkers for disease.

MASS SPECTROMETRY

Canterbury JD, Yi X, Hoopmann MR, MacCoss MJ. Assessing the dynamic range and peak capacity of nanoflow LC-FAIMS-MS on an ion trap mass spectrometer for proteomics. Analytical Chemistry 80;2008:6888–6897.

A device for high-field asymmetric waveform ion mobility spectrometry (FAIMS) is here added to the front of an ion-trap mass spectrometer to evaluate its ability to reduce isobaric interferences and mixture complexity in shotgun proteomic analysis. Unlike ion mobility spectrometry, which separates ions in packets, FAIMS acts as a filter that allows ions of a single differential mobility to pass through in a continuous manner. This is more compatible than ion mobility spectrometry with the time scale on which ions are processed in ion traps. Singly charged solvent ions and ions constituting chemical noise can be discriminated from multiply charged peptide ions. Detection of ions giving weak signals is assisted, although longer times are, of course, required to fill the trap. In analysis of a yeast cell lysate, an increase in peak capacity of 8–9× and an increase in dynamic range of > 5× is reported.

Xia Y-Q, Wu ST, Jemel M. LC-FAIMS-MS/MS for quantification of a peptide in plasma and evaluation of FAIMS global selectivity from plasma components. Analytical Chemistry 80;2008:7137–7143.

This paper demonstrates the advantage of using high-field asymmetric waveform ion mobility spectrometry (FAIMS) in quantitative measurements undertaken by single reaction monitoring in an LC-MS method using a triple quadrupole mass spectrometer. A peptide drug is quantified in a crude acetonitrile-soluble fraction of plasma, and FAIMS is shown to eliminate background ions without reducing signal-to-noise ratio for the analyte.

PROTEINS—PURIFICATION AND CHARACTERIZATION

Wagner S, Klepsch MM, Schlegel S, Appel A, Draheim R, Tarry M, Högbom M, van Wijk KJ, Slotboom DJ, Persson JO, de Gier J-W. Tuning Escherichia coli for membrane protein overexpression. Proceedings of the National Academy of Sciences, U.S.A. 105;2008:14371–14376.

To avoid problems with protein folding during over-expression of membrane proteins, it is desirable to promote accumulation in the cytoplasmic membrane rather than in inclusion bodies. Overexpression of proteins in Escherichia coli generally uses T7 RNA polymerase and a strong promoter that is recognized specifically by the T7 polymerase, with the advantage that transcription occurs 8× faster than that mediated by E. coli RNA polymerase. mRNA is therefore made in enhanced amounts. However, this strong overexpression often leads to production of more protein than the Sec translocon mediating membrane insertion can process. The result is toxic perturbation of the host membrane proteome and the appearance of inclusion bodies. The present report shows that the rate of transcription can be tuned by expressing a T7 polymerase inhibitor, T7 lysozyme, using an L-rhamnose-inducible promoter that may be controlled by supplying different amounts of L-rhamnose in the medium. Yields of overexpressed membrane protein are optimized in this system by controlling rates of translation to avoid saturating the Sec translocon, thereby avoiding the toxic effects of overexpression. In this way, protein yields are enhanced by increasing biomass rather than by maximizing the amount of specific RNA expressed by individual cells. An E. coli strain in which this system is implemented provides a convenient vehicle for high throughput optimization of membrane protein production.

Neubert H, Grace C, Rumpel K, James I. Assessing immunogenicity in the presence of excess protein therapeutic using immunoprecipitation and quantitative mass spectrometry. Analytical Chemistry 80;2008:6907–6914.

Administration of protein therapeutics may sometimes elicit immune responses against the protein drug, with deleterious clinical consequences. Measurement of circulating anti-drug antibodies in serum is sometimes complicated by the presence of high concentrations of the pharmaceutical agent itself. To circumvent this problem, a method is described in which low microliter volumes of serum are spiked with high concentrations of the drug to saturate anti-drug antibodies that are present. Immunoglobulins are then isolated with protein G magnetic beads. Stable isotope-labeled peptides with sequences mimicking those to be derived from the target therapeutic protein are added, and the protein is subjected to cyanogen bromide digestion. Peptides are then quantified by LC-MS/MS.

PROTEOMICS

Lam H, Deutsch EW, Eddes JS, Eng JK, Stein SE, Aebersold R. Building consensus spectral libraries for peptide identification in proteomics. Nature Methods 5;2008:873–875.

Spectral-library searching is expected to adopt an increasingly prominent role in proteomic data analysis relative to sequence-database searching, especially for larger-scale studies involving repeated sampling of closely related samples and targeted approaches focusing on previously observed peptides or proteins. In order to facilitate use of the methodology, an open source software suite is presented that allows investigators to build and search their own libraries from sequence search results generated by several popular search engines. The suite is integrated with the Trans Proteomic Pipeline, and uses open xML file formats. Provision is made for combining multiple observations of the same peptide and for filtering out mis-identified and poor-quality spectra. The effects of alternative strategies for performing these various manipulations are also presented. It is hoped that these software tools will assist investigators in organizing and condensing large amounts of raw data into a conveniently usable format for easy retrieval and future data analysis.

Baumgartner C, Rejtar T, Kullolli M, Akella LM, Karger BL. SeMoP: A new computational strategy for the unrestricted search for modified peptides using LC-MS/MS data. Journal of Proteome Research 7;2008:4199–4208.

Typically only 10–20% of interpretable MS/MS spectra are successfully assigned using standard search tools, owing to the accumulation of modifications from post-translational and in vitro processing. New methodology for discovering peptide modifications is presented here for implementation in shotgun proteomics workflows that use low-resolution MS/MS spectra. It is based on a three-step procedure. Firstly, a standard database search is used to identify proteins in the sample. Secondly, a comprehensive, unrestricted search for modifications conferring a mass shift of up to ± 200 Da relative to unmodified peptides is launched, using only proteins identified in the first step. For this purpose, a new algorithm that detects a constant mass shift between observed fragment ions and fragment ion mass values predicted in the absence of modifications. The algorithm requires neither identification of the corresponding unmodified peptide nor prior specification of the modification. Thirdly, the measured precursor mass is compared with the mass shift assigned in the second step as a confirmation of identified modifications. In an analysis of 65 plasma proteins, the methodology reveals a diverse set of modifications, and a 4× increase in the number of modified peptides recorded. In a cancer cell line, several new amino acid substitutions are detected. Implementation of this procedure for MS/MS spectra of high mass accuracy is expected to reap further benefits in reduction of false discovery rate.

Bantscheff M, Boesche M, Eberhard D, Matthieson T, Sweetmen G, Kuster B. Robust and sensitive iTRAQ quantification on an LTQ Orbitrap mass spectrometer. Molecular and Cellular Proteomics 7;2008:1702–1713.

Conditions for deploying multiplexed quantification using isobaric mass tags from the iTRAQ system on an Orbitrap mass spectrometer are described. Fragmentation using Pulsed-Q Dissociation (PQD) to detect product ions of low mass, which include the iTRAQ reporter ions, requires optimization of collision energy, activation Q, delay time, ion isolation width, number of microscans, and number of trapped ions to ensure adequate yield of product ions for peptide identification. However, once optimized, the data are shown to provide accurate quantification at on-column levels as low as 100 amol of a protein digest. The iTRAQ system is most commonly used with instruments offering high collision energies. However, the performance of the Orbitrap mass spectrometer using optimized PQD scanning for a complex proteome sample compares favorably with that obtained using high collision energies on a five-year-old Q-Tof Ultima mass spectrometer. Moreover, limits of quantification are better than those obtained with the “higher energy collision-induced dissociation” (HCD) scans available on the Orbitrap using the new octapole collision cell. This paper provides practical guidance for those deploying PQD scanning. It also identifies pitfalls to be avoided during quantitative proteomic analysis of ligand binding. Dose-response curves are constructed for interactions between the drug, imatinib, and cell kinases using a competition assay in which the drug competes with kinobeads for kinase binding, and errors due to inadequate characterization of the shape of competition curves are pointed out.

Han H, Pappin DJ, Ross PL, McLuckey SA. Electron transfer dissociation of iTRAQ labeled peptide ions. Journal of Proteome Research 7;2008:3643–3648.

Phanstiel D, Zhang Y, Marto JA, Coon JJ. Peptide and protein quantification using iTRAQ with electron transfer dissociation. Journal of the American Society for Mass Spectrometry 19;2008:1255–1262.

These papers address the applicability of electron transfer dissociation (ETD) to the study of iTRAQ-labeled peptides. Labeled peptides are shown to produce c- and z- fragment ions that support the identification of iTRAQ labeled peptides. The 116 and 117 tags produce the same reporter ion, so only three of the four channels available with the reagent kit are useable for multiplexed quantification. ETD yields a product ion containing both the reporter and balance groups of iTRAQ tags, but this product ion can be further fragmented by collision-induced dissociation to liberate the reporter group from which quantitative information can be derived.

Jaffe JD, Keshishian H, Chang B, Addona Ta, Gillette MA, Carr SA. Accurate inclusion mass screening: A bridge from unbiased discovery to targeted assay development for biomarker verification. Molecular and Cellular Proteomics 7;2008:1952–1962.

The majority of candidates for disease-specific protein biomarkers emerging from discovery screens are likely to be false positives. The job of distinguishing these from truly specific biomarkers during biomarker validation is best performed with assays based on multiple reaction monitoring (MRM) in which “proteotypic” peptides derived from candidate proteins are quantified using synthetic, stable isotope-labeled counterparts as internal standards. The development of such assays requires dedication of substantial resources. A method is offered here for triaging protein candidates for further study by MRM. Masses of target peptides are monitored on an Orbit-rap mass spectrometer during liquid chromatography of samples derived from the biological fluid of interest, and MS/MS spectra are acquired when a peptide from the monitored list is detected with the correct accurate mass and charge state to confirm sequence. This procedure is intended to confirm that the peptide is indeed detectable in the fluid, and indicates the likelihood of successfully developing a single-reaction-monitoring assay for the peptide. The methodology is capable of screening up to a hundred proteins per week, and is estimated to be at least 4 x more efficient at detecting peptides of interest than data-dependent scanning. The method will be of general interest to investigators utilizing targeted quantitative techniques in proteomics as well as to those involved specifically with biomarker discovery.

FUNCTIONAL GENOMICS AND PROTEOMICS

Smith DR, Quinlan AR, Peckham HE, Makowsky K, Tao W, Woolf B, Shen L, Donahue WF, Tusneem N, Stromberg MP, Stewart DA, Zhang L, Ranade SS, Warner JB, Lee CC, Coleman BE, Zhang Z, McLaughlin SF, Malek JA, Sorenson JM, Blanchard AP, Chapman J, Hillman D, Chen F, Rokhsar DS, McKernan KJ, Jeffries TW, Marth GT, Richardson PM. Rapid whole-genome mutational profiling using next-generation sequencing technologies. Genome Research 18;2008:1638–1642.

This study illustrates the power of next-generation sequencing techniques to identify mutations in whole genomes. A reference strain of the haploid yeast, Pichia stipitis, is compared to a strain selected for improved production of ethanol from xylose after chemical mutagenesis. Fewer than a dozen mutations in open reading frames are found to exist. As part of this study, performance of the 454, Solexa, and SOLiD platforms is compared, and all are found to identify each of the mutations with 10–15-fold nominal sequence coverage. Although deeper coverage will be necessary in diploid species for discovery of mutations at heterozygous loci, the approach is shown to be efficient and cost effective.

Valouev A, Johnson DS, Sundquist A, Medina C, Anton E, Batzoglou S, Myers RM, Sidow A. Genome-wide analysis of transcription factor binding sites based on ChIP-Seq data. Nature Methods 5;2008:829–834.

Jothi R, Cuppapah S, Barski A, Cui K, Zhou K. Genome-wide identification of in vivo protein–DNA binding sites from ChIP-Seq data. Nucleic Acids Research 36;2008:5221–5231.

In chromatin immunoprecipitation (ChIP), a method for identifying genomic sites of interaction with specific DNA-binding proteins, protein-DNA complexes are stabilized by cross-linking, the DNA is sheared into small fragments, and the protein is immunoprecipitated. After reversing the cross-linking, the captured DNA is analyzed either by hybridization to a tiling array or by end-sequencing using massively parallel sequencing methods. Existing methods of data analysis quantify the multiplicity of reads to identify binding regions, but the shortness of read lengths impedes localization of the exact binding site, and resolution may consequently be limited to the length of the DNA fragments being sequenced. The two papers cited here provide algorithms for precise identification of binding sites by exploiting the direction of reads to estimate fragment length and then use the direction of reads and fragment length to narrow down thee binding site to a few tens of nucleotides. Both studies indicate that read density can be used as a measure of binding affinity of the protein for DNA, and document many new sites of interaction for the proteins studied.

Typas A, Nichols RJ, Siegele DA, Shales M, Collins SR, Lim B, Braberg H, Yamamoto N, Takeuchi R, Wanner BL, Mori H, Weissman JS, Krogan NJ, Gross CA. High-throughput, quantitative analyses of genetic interactions in E. coli. Nature Methods 5;2008:781–787.

Butland G, Babu M, Díaz-Mejía JJ, Bohdana F, Phanse S, Gold B, Yang W, Li J, Gagarinova AG, Pogoutse O, Mori H, Wanner BL, Lo H, Wasniewski J, Christopolous C, Ali M, Venn P, Safavi-Naini A, Sourour N, Caron S, Choi JY, Laigle L, Nazarians-Armavil A, Deshpande A, Joe S, Datsenko KA, Yamamoto N, Andrews BJ, Boone C, Ding H, Sheikh B, Moreno-Hagelseib G, Greenblatt JF, Emili A. eSGA: E. coli synthetic genetic array analysis. Nature Methods 5;2008:789–795.

Study of double mutants has long facilitated functional gene annotation through discovery of components of pathways or complexes. Genome-wide methods for screening double mutants are available for eukaryotes. An example is synthetic genetic array analysis in Saccharomyces cerevisiae, and the use of such methods has resulted in identification of nearly 20,000 synthetic lethal gene interactions. By contrast, lack of comparable screening techniques for prokaryotes has limited the number of known synthetic lethals in E. coli to less than 200, even though the genome is of similar size. The two papers reviewed here present methods for high-throughput generation of double mutants in E. coli. They both employ gene transfer by the Hfr conjugation system. A drug-resistance-marked query gene mutation from a donor strain is transferred into a genome-wide collection of single-gene mutant recipients in a high-density array. Dual marker selection for double mutants then permits phenotypes to be documented by colony imaging. This methodology is anticipated to provide extensive new information about functional relationships and modularity in prokaryotes.

IMAGING

Resch-Genger U, Grabolle M, Cavaliere-Jaricot S, Nitschke R, Nann T. Quantum dots versus organic dyes as fluorescent labels. Nature Methods 5;2008:763–775.

This review summarizes the considerations involved in choosing whether to use the relatively new quantum dot technology or to employ conventional fluorescent organic dyes for a given imaging or sensing task. Quantum dots are inorganic nanocrystals whose absorption and emission can be tuned by changing particle size. They have many favorable properties, including broad and intense absorption bands, high quantum yield in fluorescence emission, good photochemical stability, and strong potential for multiplexing. Nevertheless, few quantum dot systems have thus far become commercially available, and data on reproducibility and potential for quantification are sparse. Organic fluorophores, by contrast, are inexpensive and widely available; their characteristics are well understood and functionalization protocols are well established. The behavior of quantum dots as colloids rather than solutions imposes extra complexity on their application, and conditions for their use are still identified individually rather than formulaically. However, future developments will undoubtedly facilitate the application of quantum dots. The review includes consideration of issues related to solubilization, cellular targeting, stability, toxicity, and fluorescence resonance energy transfer (FRET) that will be of general interest to investigators planning imaging/ sensing studies.


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