Article ID: WMC002580 2046-1690

Genomics in Medical Science: An Overview

Corresponding Author: Mr. Robby Kumar, Lecturer, SSR Medical College, Mauritius - Mauritius

Submitting Author: Mr. Robby Kumar, Lecturer, SSR Medical College, Mauritius - Mauritius

Article ID: WMC002580 Article Type: Review articles Submitted on:04-Dec-2011, 08:33:21 PM GMT Published on: 05-Dec-2011, 08:44:24 AM GMT Article URL: http://www.webmedcentral.com/article_view/2580 Subject Categories:BIOTECHNOLOGY Keywords:Genomics, Epigenomics, Toxicogenomics, , MicroRNomics, Pharmacogenomics How to cite the article:Kumar R . Genomics in Medical Science: An Overview . WebmedCentral BIOTECHNOLOGY 2011;2(12):WMC002580 Source(s) of Funding: None

Competing Interests: None

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Genomics in Medical Science: An Overview

Author(s): Kumar R

Abstract infectious diseases. This is clearly illustrated during the severe acute respiratory syndrome (SARS) outbreak in 2002–2003 and the emergence and worldwide spread of the pandemic H1N1 2009 Genomics is the study of an organism's genome and influenza virus this year. In both cases, genomics the use of the . It deals with the systematic use played a key role in the immediate response to the of genome information, associated with other data, to outbreak. Initially, very little was known about the virus provide answers in biology, medicine, and industry. responsible for the SARS outbreak. Pangenomic virus Genomics has the potential of offering new therapeutic microarrays identified it as a coronavirus (6); however, methods for the treatment of some diseases, as well it was only through detailed sequencing that the as new diagnostic methods. Other applications are in specific genotype of this virus could be determined (7). the food and agriculture sectors. The major tools and Comparative sequence analysis identified the SARS methods related to genomics are bioinformatics, virus as distinct from other coronaviruses in terms of genetic analysis, measurement of expression, its encoded proteins responsible for antigen and determination of gene function. presentation. This finding ultimately lead to Introduction development of diagnostics (8) and potential therapeutics (9). This example of a sequencing approach as a rapid response to a virus outbreak Human genomics, the study of structure, function, and demonstrates that genomics can be a useful and interactions of all genes in the , important, if not essential, epidemiological tool. In the promises to improve the diagnosis, treatment, and ongoing H1N1 influenza outbreak, the National Center prevention of disease. This is due to the result of the for Biotechnology Information (NCBI) established the completion of the Human Genome Project. It is Influenza Virus Resource, containing 462 complete anticipated that genomics will bring to physicians a viral genome sequences from worldwide viral samples. powerful means to discover hereditary elements that Some of the genomic data was completed, compared, interact with environmental factors leading to disease and released to the public within two weeks of (1). The ‘‘Genomic Revolution’’ has transformed our isolation of the DNA. The rapid generation of genome vision and understanding of how living organisms and sequence data is providing a paradigm shift in the systems interact with each other and with the analysis of infectious disease outbreaks, from more environment (2). Increasingly, the science of genomics classical methods of isolation to the rapid molecular serves as the foundation for translational research for examination of the pathogen in question.(9) advancing the management of many important The fundamental idea that responses to environmental diseases (3). factors or treatments is to be found in our individual differences, the underlying concept of “genomic Genomics and Infectious medicine”, is rooted in antiquity and based on disease: Current status millennia of simple observation. The objective of genomic medicine is to determine the genetic bases of those differences in response to environmental agents, including medications, and differences that may Infectious disease management is also transforming predispose to the development of common and thanks to molecular technologies as seen in HIV (4,5), potentially personally devastating and societally tuberculosis, malaria , and other neglected tropical expensive disorders, and to use them in populations to diseases . Discovering novel pathogens and thwart adverse response, increase the frequency of elucidating the implications of genetic variation among beneficial response, and intervene to prevent or delay existing pathogens is critical for rapidly mitigating onset of disease.(10) Approximately 1100 different pandemic threats, as demonstrated recently with genes have been shown to have at least one mutation severe acute respiratory syndrome (SARS) and avian in them that causes a disease. Total number of (H5N1) and pandemic H1N1 2009 influenza(3). disease genes = approx. 1500 (11) H1N1 2009 Influenza: Genomics. Genomics can be readily applied to follow outbreaks of

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Functional Genomics potential disease gene, and we end up with the new concept of 'reverse medicine', by which we will derive new morbid entities and pathogenic pathways from the knowledge of the structure and function of every Understanding the function of genes and other parts of gene.(16) Identifying all of the human genes is but one the genome is known as functional genomics. step in understandingdisease pathogenesis. These Functional genomics is a field of molecular biology that new proteinsfunction (and malfunction) in novel and is attempting to make use of the vast wealth of data complex metabolic pathways should be seen.While produced by genome sequencing projects to describe the human genome sequence gives us a road map, genome function. Functional genomics uses sensitive much workremains in understanding where the road techniques like DNA microarrays, proteomics, leads and what detoursmay exist. There is a metabolomics and mutation analysis to describe the complex,multigenic disorders that are responsible for function and interactions of genes.(12) some of the most commonmaladies in society such as The development and application of global (genome- atherosclerosis, hypertension, diabetes,psychiatric wide or system- wide) experimental approaches to disorders, and stroke. (17,18) assess gene function by making use of the information Toxicogenomics and reagents provided by structural genomics [in the Current goals of toxicogenomics, which would also be original more limited sense of construction of high- relevant to immunotoxicology, include hazard resolution genetic, physical and transcript maps of an identification by comparing microarray results with organism. It is characterized by high throughput or analyses of structure activity relationships or animal large- scale experimental methodologies combined bioassays, risk characterization by coupling genomic with statistical and computational analysis of the data with population exposure assessment or results. The fundamental strategy is to expand the cross-species comparisons provide a template that scope of biological investigation from studying single immunotoxicologists may apply to reach these same genes or proteins to studying all genes or proteins at goals.(21) One of the most likely immune mediated once in a systematic fashion.(13) adverse effects of chemical exposure is Human Genome Project hypersensitivity, researchers have shown the The Human Genome Project, which was led at the development of an in vitro approach to detect potential National Institutes of Health (NIH) by the National contact allergens by following in cells Human Genome Research Institute, produced a very exposed to a known strong sensitizer or irritant. high-quality version of the human genome sequence Changes in gene expression by that is freely available in public databases. That dinitrosulphobenzene-activated dendritic cells international project was successfully completed in generated from CD14+ adherent human mononuclear April 2003, under budget and more than two years cells identified 29 candidate target genes important in ahead of schedule. The sequence is not that of one the response to sensitizing agents (22) Genomics has person, but is a composite derived from several been used successfully to study mechanisms of action individuals. Therefore, it is a "representative" or (specific pathways associated with immunotoxicity of a generic sequence. To ensure anonymity of the DNA specific chemical).(21) donors, more blood samples (nearly 100) were MicroRNomics collected from volunteers than were used, and no RNomics is studysncRNAs on the genomic scale (23). names were attached to the samples that were The standard pathway of informationflow in a cell from analyzed. Thus, not even the donors knew whether DNA to message RNA (mRNA) to protein hasbeen the their samples were actually used. The Human dominant theme in molecular biology. However, Genome Project was designed to generate a resource recentanalyses of the human and animal genomes that could be used for a broad range of biomedical have demonstrated thatthe majority of RNA transcripts studies.(14,15) The major impact of the completion of are not protein coding RNAs(mRNAs), but noncoding the human genome sequence is the understanding of RNAs (ncRNAs) (24) Indeed,large-scale disease etiology with deduced therapy. The catalog of complementary DNA sequencing and genome tiling monogenic diseases should be easily completed arraystudies have shown that 50% of genomic DNA in through in silico cloning. The major challenge today is humans is transcribedinto RNA transcripts, of which to decipher the polygenic and multifactorial etiology of 2% is translated into proteinsand the remaining 98% is common diseases, such as cancer, cardiovascular, ncRNAs (24). In general,the sizes of the majority of nutritional, allergic, auto-immune, degenerative ncRNA species vary from 18 nt to500 nt, well below disorders. In fact every gene, when mutated, is a the size of the majority of mRNA species,and are

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therefore termed small ncRNAs (sncRNAs). The term genomic scale has motivated the development of ncRNAis commonly employed for RNA that does not high-throughput technologies for macromolecular encode a protein,but this does not mean that such structure determination, which have begun to produce RNAs do not contain informationor have function (24). structures at a greater rate than previously possible. For example, ribosomalRNAs and transfer RNAs, These new structures have revealed many which make up a large proportion ofRNA based on unexpected functional and evolution relationships that amount, are two known sncRNAs that provide helpfor were hidden at the sequence level.(26) Structural protein expression. Quite recently, two novel classes genomics, by design, is a hypothesis-generating ofsncRNAs were discovered: microRNAs (miRNAs) instead of a hypothesis-driven endeavor. It shares this and small interferingRNAs (siRNAs). miRNAs and aspect with many new high-throughput genomics siRNAs have similar sizes (18–23 nt) and sharethe projects in the evolving molecular biology discipline similar mechanisms of gene expression regulation. although— unlike other genomics projects—structural However,their biogenesis and origins are different. genomics continues to generate very high resolution, siRNAsare produced from long, double-stranded detailed molecular data.(27) (bimolecular) RNAs,or long hairpins, often of The ultimate goal of structural genomics is to obtain exogenous origin, and usually targetsequences at the the structure of each protein coded by each gene same locus or elsewhere in the genome for within a genome to determine gene function. Because destruction(gene silencing). In contrast, miRNAs are of cost and time limitations, it remains impractical to endogenous. They areencoded within the genome and solve the structure for every gene product come from endogenous short hairpinprecursors and experimentally. Up to a point, reasonably accurate usually target sequences at other loci. three-dimensional structures can be deduced for Therefore,miRNAs may be more important because proteins with homologous sequences by using they are endogenous regulatorsof gene expression. comparative modeling. Beyond this, fold recognition or Microarray analysis of miRNAs on the genome scale is threading methods can be used for proteins showing the mostpowerful method in microRNomics to little homology to any known fold, although this is determine the expressionsignature of cells, tissues, relatively time-consuming and limited by the library of and organs within an organism underdifferent template folds currently available.(28) conditions. Expression profiles have recently been Eukaryotic proteins (particularly those from humans generated and diagnosed by microarrayanalysis in and higher vertebrates) are difficult targets for chronic lymphocyticleukemia (CLL), breast, colon, lung, structural genomics because of a number of factors. (a) pancreatic endocrine, pancreatic adenocarcinoma, The gene models for eukaryotic proteins are poorly prostate, stomach, and glioblastomas, cardiovascular developed. (b) Eukaryotic proteins contain a large diseases and many more leathal conditions.These number of introns and are subject to alternative microRNomic approaches reveal that a large number splicing patterns. (c) Eukaryotic proteins frequently of miRNAsare aberrantly expressed in diverse cancers. require chaperones for proper folding. (d) Eukaryotic The majority ofthese dysregulated miRNAs are proteins contain considerably more regions of intrinsic targeted at either oncogenes ortumor-suppressing disorder, and a large fraction of them (~60%) are fully genes. As tissue and cell-specific expressionis an natively disordered. (e) Because of difficulties in important feature for miRNAs, these bioinformatic producing and solubilizing them, few structures of measurementsof expression profiles are useful to recombinant eukaryotic membrane proteins have been identify and diagnose humancancers. It is well known determined.(29) that some miRNAs are critical regulatorsfor cell differentiation, and identification of these key miRNAs'expression signatures could be an alternative way to evaluatecancer progression and prognosis.(25) Comparative genomics is the analysis and comparison Structural Genomics of genomes from different species. The purpose is to gain a better understanding of how species have evolved and to determine the function of genes and Structural genomics aims to delineate the total noncoding regions of the genome. Researchers have repertoire of protein folds, thereby providing learned a great deal about the function of human three-dimensional portraits for all proteins in a living genes by examining their counterparts in simpler organism and to infer molecular functions of the model organisms such as the mouse. Genome proteins. The goal of obtaining protein structures on a researchers look at many different features when

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comparing genomes: sequence similarity, gene activity and expression that are not dependent on location, the length and number of coding regions gene sequence. For purposes of this program, (called exons) within genes, the amount of noncoding epigenetics refers to both heritable changes in gene DNA in each genome, and highly conserved regions activity and expression (in the progeny of cells or of maintained in organisms as simple as bacteria and as individuals) and also stable, long-term alterations in complex as humans.(30) For genetics and the transcriptional potential of a cell that are not development, for immunology and pharmacology, for necessarily heritable. While epigenetics refers to the cancer and heart disease, even for behaviour, learning study of single genes or sets of genes, epigenomics and memory and psychiatric disorders (31,32) the refers to more global analyses of epigenetic changes laboratory mouse has become an indispensable tool. across the entire genome.(38) From Sequence of the human genome it appears to Epigenetic mechanisms are affected by several factors have far fewer protein-coding genes(less than 30,000) and processes including development in utero and in than accepted 80,000–100,000. Analysis of the mouse childhood, environmental chemicals, drugs and genome backs up this finding. The sequencing pharmaceuticals, aging, and diet. DNA methylation is consortium estimates that it contains 27,000–30,500 what occurs when methyl groups, an epigenetic factor protein-coding genes. Ninety-nine per cent of these found in some dietary sources, can tag DNA and genes have a sequence match in the human genome activate or repress genes. Histones are proteins and 96% of these lie within 'syntenic' regions of mouse around which DNA can wind for compaction and gene and human chromosomes.(33) Based on pairwise regulation. Histone modification occurs when the alignments of nearly 13,000 (out of about 28,000) binding of epigenetic factors to histone “tails” alters the orthologous gene pairs, the consortium found that the extent to which DNA is wrapped around histones and encoded proteins had a median amino-acid sequence the availability of genes in the DNA to be activated. All identity of 78.5%. In comparison, orthologous mouse of these factors and processes can have an effect on and rat proteins are, on average, 97% identical(34), people’s health and influence their health possibly and a sample of human and Caenorhabditis elegans resulting in cancer, autoimmune disease, mental (nematode) proteins had an average of 49% of their disorders, or diabetes among other illnesses. amino acids in common (35) epigenetic modifications to chromatin, include 5' Knockout mice are transgenic mice whose genetic methylation of the cytosine residue in CpG code has been altered by the insertion of foreign dinucleotides of Dna, covalent modifications (including genetic material into their DNA. Using this technology, methylation, acetylation, phosphorylation and researchers target specific genes --causing them to be ubiquitination) of histones, the proteins that package expressed or inactivated. These mice are then bred Dna into chromatin, and the gene-regulating and ch --creating a population of offspring with the trait. romatinorganizing activities of noncoding rnas. these When researchers isolate human genes with unknown epigenetic modifications change the binding of functions, they can create knockout mice with these transcription activators and repressors to specific gene genes and observe the results. Instead of creating promoters, and/or alter the large-scale conformation merely the mouse equivalent of the human gene, and function of chromatin itself, which modulates gene researchers are able to reproduce and express actual expression, the best- studied examples of human genes and their corresponding proteins in mice. developmental epigenetic processes in mammals Subsequent offspring will inherit not only the include X-chromosome inactivation in females and instructions coded by their original mouse genome, but parent- specific expression of imprinted genes.(39,40) also the traits coded for by the inserted human DNA. in general, Dna methylation seems to be involved in This helps researchers understand health and disease long-term silencing of gene expression, Whereas by observing how genes work in cells. Knockout mice histone modifications have a short-term and flexible have many benefits. They not only allow researchers effect, but substantial crosstalk exists between these to determine gene function and understand diseases different mechanisms.(41,42) The epigenomics can at the molecular level, but they also aid scientists in predict the high rik diseases such as cardiovascular testing new drugs and devising novel therapies. (30,33) diseases, cancer and diabetes mellitus by seening epigenomic markers, such as methylation patterns in Epigenomics specific gene promoters, may enable the identification of individuals who will have increased susceptibility to chronic disease in adulthood because of adverse Epigenetics is an emerging frontier of science that factors in their early environment. After identification of involves the study of changes in the regulation of gene such individuals may allow the prevention of disease,

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either by lifestyle modification or by active nutritional or pathogen virulence and evolution. Enabling pharmacological intervention.(42,43,44,45) technologies and bioinformatics tools have shifted genomics from a separate research discipline to a tool Pharmacogenomics so powerful that it can provide novel insights that were not imaginable a few years ago, including for example redefining the notion of strains or cultures in the The term pharmacogenomics describes a polygenic or context of biopreparedness or microbial forensics. genome-wide approach to identifying genetic Challenges remain, though, mostly in the form of large determinants of drug response, utilizing both amounts of data that are being generated, and will information from the human genome project and continue to be generated in the future, and are technologies such as high throughput sequencing, becoming difficult to manage. The need for better DNA and protein microarrays, and bioinformatics. bioinformatic algorithms, access to faster computing Improving therapeutic efficacy and reducing drug capabilities, larger or novel and more efficient data toxicity are two of the most important goals of storage devices, and better training in genomics are all genomics and genetics in clinical practice.(46) in critical demand, and will be required to fully Benefits of pharmacogenomics include: embrace the genomic revolution.(9) There are several a) Powerful and improved Drugs/Medicines: areas of new knowledge that will have to be developed Pharmaceutical companies will be able to create drugs to create a reality of genomic medicine. These include based on the proteins, enzymes, and RNA molecules the characterization of genomic variation among associated with genes and diseases. This will facilitate individuals in the target populations (and each drug discovery and allow drug makers to produce a separate population will probably have to be studied therapy more targeted to specific diseases. This anew), the identification of the clinically significant accuracy not only will maximize therapeutic effects but variants in each group, the assessment of the extent also decrease damage to nearby healthy cells. to which intervention could change predicted b)Determining Appropriate Drug Dosages: Current outcome–taking into account other changes in methods of basing dosages on weight and age will be environmental exposure and behaviors, and the replaced with dosages based on a person's genetics development of an understanding of the costs of these --how well the body processes the medicine and the processes for the society and weighing them against time it takes to metabolize it. This will maximize the other societal needs.(10) Selecting strategies for therapy's value and decrease the likelihood of monitoring the DNA variations associated with human overdose. disease requires careful consideration and new c)Screening for Disease: Knowing one's genetic innovative methodologies. First, the cost of detecting code will allow a person to make adequate lifestyle DNA variations is still too high to enable screening for and environmental changes at an early age so as to tens of thousands of SNPs in massive epidemiological avoid or lessen the severity of a genetic disease. study samples. Second, the annotation and cataloging Likewise, advance knowledge of a particular disease of variations and their frequencies in various susceptibility will allow careful monitoring, and populations is not systematically organized. Third, the treatments can be introduced at the most appropriate selection of relevant variants for epidemiological and stage to maximize their therapy. functional studies is still a guessing game. We know d)Better Vaccines: Vaccines made of genetic amazingly little about the relative importance of material, either DNA or RNA, promise all the benefits variations in the regulatory and intronic sequences of of existing vaccines without all the risks. They will human genes and how they differ between populations. activate the immune system but will be unable to Fourth, quantitative analyses of the effects of cause infections. They will be inexpensive, stable, thousands of DNA variations and the "genome-wide" easy to store, and capable of being engineered to variant profiles that predispose individuals to complex carry several strains of a pathogen at once. (30,47) diseases are still in their infancy. All of these issues require methodological developments, coordinated Conclusion efforts, and better solutions than those currently available to genetic epidemiologists.(11) We are rapidly advancing upon the postgenomic era in which The field of biodefense has thoroughly embraced genetic information will have to be examined in genomics and made it a keystone for developing multiple health care situations throughout the lives of better identification technologies, diagnostic tools, and individuals. Currently, newborn babies can be vaccines and improving our understanding of screened for treatable genetic diseases such as

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Reviews Review 1

Review Title: Genomics in Medical Science: An Overview

Posted by Dr. Dave Siak-Wei Ow on 16 Dec 2011 09:13:55 AM GMT

1 Is the subject of the article within the scope of the subject category? Yes 2 Are the interpretations / conclusions sound and justified by the data? Yes 3 Is this a new and original contribution? Yes 4 Does this paper exemplify an awareness of other research on the topic? Yes 5 Are structure and length satisfactory? Yes 6 Can you suggest brief additions or amendments or an introductory statement that will increase No the value of this paper for an international audience? 7 Can you suggest any reductions in the paper, or deletions of parts? No 8 Is the quality of the diction satisfactory? No 9 Are the illustrations and tables necessary and acceptable? Yes 10 Are the references adequate and are they all necessary? Yes 11 Are the keywords and abstract or summary informative? Yes

Rating: 6 Comment: Comments:

An overall general review on current directions after the completion of the human genome. On the whole, this review is informative and clear despite some typing errors that need to be corrected. Otherwise, I feel that there author could be too positive on the assessment of the promises of the field and could be more critical and mentioned on several limitations and shortcomings. For instance:

On Comparative Genomics(page 5) – while the numbers of protein-coding genes in human comparable to the mouse and is small in the region of 30,000, and 99% of mouse genes have a sequence match in human, it should be noted that differences at the actual individual protein levels should be significantly more pronounced due to differences in alternative splicing between the two organisms and different post translational modifications (refer to http://www.uniprot.org/docs/ptmlist for list of known post translational modifications) resulting in millions of species-unique protein species each possessing different functions. Hence, there are limits as well as merits to the use of knockout mouse models for understanding human diseases and metabolism.

On Genetic vaccines (page 6) –While, DNA vaccines is indeed promising as a possible low-cost alternative to conventional inactivated or attenuated forms of causive pathogens, currently immunogenic efficiency is still low and cost-effective gene delivery to patients are areas that needs to be work on.

Minor diction comments Page 1 – Under “How to cite the article:” Remove extra space between “overview” and period.

Page 2 – First sentence under “Genomics and Infectious disease: Current status” – Remove extra space at the end of sentence.

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Page 3 – Paragraph 2, sentence 1 under “Functional Genomics” – Either remove “[“ or replace with open “(“ and close “)” brackets

Page 3 – “RNomics is study of sncRNAs on the genomic scale” instead of “RNomics is studysncRNAs on the genomic scale”. Additionally, sncRNAs (small noncoding RNAs) could be defined the first time this term is used rather than having the definitions found in sequentially in the same paragraph.

Page 4-6 – There are several missing spaces in sentences prohibiting reading clarity. The author should recheck and amend.

Page 5 – Last paragraph – “high risk” instead of “high rik”

Page 7 and 9 - Reference section: Inconsistent referencing style used.

Competing interests: None Invited by the author to make a review on this article? : No Experience and credentials in the specific area of science: Proteomics, Microarrays, DNA vaccines

Publications in the same or a related area of science: No How to cite: Ow D.Genomics in Medical Science: An Overview [Review of the article 'Genomics in Medical Science: An Overview ' by ].WebmedCentral 1970;2(12):WMCRW001272

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Review 2

Review Title: Genomics in Medical Science: An Overview

Posted by Dr. Govind N Purohit on 12 Dec 2011 06:06:56 AM GMT

1 Is the subject of the article within the scope of the subject category? Yes 2 Are the interpretations / conclusions sound and justified by the data? Yes 3 Is this a new and original contribution? Yes 4 Does this paper exemplify an awareness of other research on the topic? Yes 5 Are structure and length satisfactory? Yes 6 Can you suggest brief additions or amendments or an introductory statement that will increase No the value of this paper for an international audience? 7 Can you suggest any reductions in the paper, or deletions of parts? No 8 Is the quality of the diction satisfactory? Yes 9 Are the illustrations and tables necessary and acceptable? Yes 10 Are the references adequate and are they all necessary? Yes 11 Are the keywords and abstract or summary informative? Yes

Rating: 7 Comment: The Conclusion in the manuscript is too long and not pointing out the future direction. The authors should exclude references in the conclusions section and conclude the status of research instead of discussing the conclusions.

Competing interests: No Invited by the author to make a review on this article? : No Experience and credentials in the specific area of science: no

Publications in the same or a related area of science: No How to cite: Purohit G.Genomics in Medical Science: An Overview[Review of the article 'Genomics in Medical Science: An Overview ' by ].WebmedCentral 1970;2(12):WMCRW001232

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