semantic presentation of a given journal article the PDF format can serve as a medium to distribute compact, platform- independent documents that are easy to read and print. Even today, primary documents as PDF and Microsoft Word files can store XML (metadata) as part of the document structure [63], and molecular drawing software programs such as Chem- Writer, GChemPaint and ACD ChemSketch can attach the molecular connection table to the graphics [64]. Next-generation MS Word implementations will encode chemical structures and more important chemical reaction data directly in the MS Word document format (Chem4Word) [65]. In this way it will be possible to store and expose chemical information in a semantically rich manner and support data mining scenarios for authors, readers and publishers. Hence every chemistry publication will be automatically structure searchable. The semantic annotation tool Oscar3 could then be used to annotate publications in high-throughput mode with additional XML data and add semantics and ontology support [66]. Client side applications for web browsers will be used which enrich published chemistry texts using resource description frameworks (RDF) and web ontology languages [67] and would profit from additional metadata. For past publications, high quality OCR techniques will still be needed using chemical structure recognition algorithms like OSRA [68], Kekule [69], CLiDE [70], ChemOCR [54] and ChemReader [71] as well as additional name-to-structure and structure-to-name approaches. However, the current approach of parsing peer-reviewed literature to obtain structures and important spectral data sets from bitmap data is not keeping up with the today’s technological possibilities. Small molecule reports need to disclose sample metadata and absolute concentrations Metabolite concentrations should be annotated with correct taxonomical and biological metadata, e.g. for the organs, cells, liquids or subcellular compartments that were studied. Stricter rules for publications have long been established in genomic research which requires submission to standard repositories to GenBank [60] and submission of gene expression or microarray data to the Gene Expression Omnibus (GEO) database. That is not the case in chemistry, biochemistry and metabolomics. As the NCBI taxonomy database [29] is linked to PubChem, each of the 300,000 unique taxonomic species in NCBI could potentially be annotated with PubChem data and fulltext PubMed Central data if this is financially, legally and administratively supported by NIH. An alternative solution would require that journals perform annotation of compounds and annotation within PubChem automatically. Working solutions are already implemented in some of the Nature journals (Nature Chemical Biology and Nature Chemistry) which submits all chemical structures to PubChem and in the RSC Project Prospect which performs online annotations of chemicals and ontology data [59] and substances with their articles DOI links can be searched via ChemSpider. With such metadata and additional information on absolute (molar) concentrations, researchers could query reports for cross-species, cross-organ and cross-study comparisons. When relative metabolite changes are reported, comparisons between different analytical platforms are not feasible unless a unified reference sample would be used. Benefits of authoritative data repositories How would the implementation of these publication standards benefit researchers and remove the obstacles to retrieve the current knowledge on a species metabolome? Batch downloads from repositories will immediately become easier and richer, Data Exchange in Chemistry once small molecule reports are machine readable with PubChem CIDs and chemical structures. Chemistry search engines like ChemSpider will collate information and make it widely available, similar to current public databases like MetaCyc and PubChem. Unfortunately, many database suppli- ers will continue to have financial or legal restrictions that prevent large public downloads. Even if open access may eventually decrease the importance of proprietary databases, funding and curating open access databases will remain a problem, potentially resulting in a difference between public and privileged database access. Therefore, publications with elec- tronic metadata and structures can only be the first step to improve data accessibility. We are convinced that such strategies will change the structure of existing databases in a very short time frame. For example, BioCyc has recently added PubChem identifiers and also KEGG is fully linked, but had not supported PubChem initially. Ultimatively authoritative data repositories are needed just like GenBank or the Gene Expression Omnibus (GEO) database. Differentiation between endogenous and exogenous metabolites The differentiation between endogenous and exogenous metabolites is far more difficult. In-silico approaches based on orthology mapping or computational approaches, i.e. the RiceCyc and KEGG databases, contained the largest computa- tionally compiled for rice metabolites, many of which are supposed to occur in samples. Until recently, lipids were mostly absent from pathway databases but are now included due to the new LipidMaps repository [35]. KEGG contained most of the polar and non polar lipids with general coverage of around 1,500 lipids mostly obtained from LipidMaps. It is important to test experimentally (using analytical chemistry tools) whether these metabolites and pathways are actually correctly predicted by pathway databases. Tools exist like the Pathway Tools Omics- Viewer [47] which allow the mapping of experimental data of identified metabolites onto pathways. Conversely, once novel metabolites are unambiguously identified in species like rice, it is important that genome databases provide tools to suggest potential enzymes and genes that could link these novel metabolites to known pathways via a minimum set of chemical transformations. Such efforts would only be possible if structure information is encoded in InChI formats and supported by genome database providers. Related efforts have been reported on ‘atomic reconstruction maps’ which are constructed on a substructure level [48] and carbon-fate maps for metabolic reactions [49]. Only four experimental data repositories resulted in hits excluding xenobiotic compounds, SetupX/BinBase, Dr. Duke, DNP and KNApSAcK DB. However, the number of retrieved metabolites was very small for these databases and thus very likely cover only a small fraction of the real size of the rice metabolome. Conversely, databases like CAS, PubChem and Beilstein con- tained a large number of metabolites, but results were mixed with drugs or pesticides and thus also do not allow compiling an overview of genuine rice metabolites. Unfortunately, our sugges- tions for changes in publication standards will not solve the relationship of ‘chemicals’ in the reports to the specific organisms, as this would require some form of ontology or hierarchy in the database entries as well as in journal reports. While in plants, most (but not all) experimentally detected small molecules can be assumed to be synthesized by the plant biochemical machinery, such assumption is certainly not true in humans. For animals, the distinction between exogenous and endogenous metabolites is far PLoS ONE | www.plosone.org 7 May 2009 | Volume 4 | Issue 5 | e5440