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• v.47(Database issue); 2019 Jan 8

The 26th annual Nucleic Acids Research database issue and Molecular Biology Database Collection

Daniel j rigden.

1 Institute of Integrative Biology, University of Liverpool, Crown Street, Liverpool L69 7ZB, UK

Xosé M Fernández

2 Institut Curie, 25 rue d’Ulm, 75005 Paris, France

The 2019 Nucleic Acids Research (NAR) Database Issue contains 168 papers spanning molecular biology. Among them, 64 are new and another 92 are updates describing resources that appeared in the Issue previously. The remaining 12 are updates on databases most recently published elsewhere. This Issue contains two Breakthrough articles, on the Virtual Metabolic Human (VMH) database which links human and gut microbiota metabolism with diet and disease, and Vibrism DB, a database of mouse brain anatomy and gene (co-)expression with sophisticated visualization and session sharing. Major returning nucleic acid databases include RNAcentral, miRBase and LncRNA2Target. Protein sequence databases include UniProtKB, InterPro and Pfam, while wwPDB and RCSB cover protein structure. STRING and KEGG update in the section on metabolism and pathways. Microbial genomes are covered by IMG/M and resources for human and model organism genomics include Ensembl, UCSC Genome Browser, GENCODE and Flybase. Genomic variation and disease are well-covered by GWAS Catalog, PopHumanScan, OMIM and COSMIC, CADD being another major newcomer. Major new proteomics resources reporting here include iProX and jPOSTdb. The entire database issue is freely available online on the NAR website ( https://academic.oup.com/nar ). The NAR online Molecular Biology Database Collection has been updated, reviewing 506 entries, adding 66 new resources and eliminating 147 discontinued URLs, bringing the current total to 1613 databases. It is available at http://www.oxfordjournals.org/nar/database/c .

NEW AND UPDATED DATABASES

The Nucleic Acids Research (NAR) Database Issue reaches its 26th annual issue in 2019. As ever, the 168 papers within cover the full range of biological research. Among them, entirely new databases account for 64 (Table ​ (Table1) 1 ) while 92 cover resources that have previously appeared in the Issue and now return with updates. The remaining 12 papers are updated on databases last published elsewhere (Table ​ (Table2). 2 ). The usual categorization is again used: after reports from the major resource collections at the U.S. National Center for Biotechnology Information (NCBI), the European Bioinformatics Institute (EBI) and the BIG Data Center at the Beijing Institute of Genomics, Chinese Academy of Sciences there are these groupings: (i) nucleic acid sequence and structure, transcriptional regulation; (ii) protein sequence and structure; (iii) metabolic and signaling pathways, enzymes and networks; (iv) genomics of viruses, bacteria, protozoa and fungi; (v) genomics of human and model organisms plus comparative genomics; (vi) human genomic variation, diseases and drugs; (vii) plants and (viii) other topics, such as proteomics databases. Many interdisciplinary databases defy easy categorization, encouraging readers to browse the whole issue. The NAR online Molecular Biology Database Collection, classifies databases more finely using 15 categories and 41 subcategories, and can be found at http://www.oxfordjournals.org/nar/database/c .

Descriptions of new online databases in the 2019 NAR Database issue

a For full references to the databases featured in this issue, please see the Table of Contents.

Updated descriptions of databases most recently published elsewhere

Among the major global centers, the NCBI ( 1 ) reports on new and expanded literature resources, including PubMed Labs ( 2 ) a new interface to PubMed, and new sequence database search options. The EBI paper ( 3 ) reports on the new databases Single Cell Expression Atlas and PDBe-Knowledgebase. The latter encompasses FunPDBe, an initiative to better harness structural bioinformatics methods and international collaborators to annotate the protein structural data in PDBe. An interesting facility reported by the BIG Data Center paper ( 4 ) is their BIG Search which not only scans across the Center’s many resources but accesses indexes from non-Center partner databases on topics as diverse as lncRNAs, plant transcription factors and autophagy-related proteins.

Major returning resources in the ‘Nucleic acid databases′ section include miRBase ( 5 ) which focuses on criteria to assess the reliability of microRNA entries and functional annotation from linked target predictions, external manual curation and text mining. For long non-coding RNAs and their targets, LNCipedia ( 6 ) contributes an update, also with a major focus on text mining and manual curation. The popular LncRNA2Target database ( 7 ) reports a new release with major increases in lncRNAs, targets and lncRNA–target associations. Two papers address piRNAs (the returning piRBase; 8 ) or their targets (the newcomer piRTarBase; 9 ). The RNAcentral ( 10 ) hub now retrieves ncRNA data from a total of 28 databases. Important progress since the last paper is reported in mapping genome locations, quality control using the Rfam database ( 11 ) and functional annotation. Elsewhere two new databases—Plasmid Atlas ( 12 ) and PLSDB ( 13 )—allow easy analyses and searches against the ever-increasing number of bacterial plasmid sequences. In resources for transcription factors (TFs), AnimalTFDB ( 14 ) now covers 97 animal genomes and includes a variety of new data such as links from TF-SNP pairs to GWAS data, TF gene expression data and protein-protein interaction networks involving TFs. An interesting new database MethMotif ( 15 ) integrates TF binding sites with data on DNA methylation, demonstrating the cell type specificity of many TFs in terms of both binding site sequences and methylation profiles.

In the section on protein sequence and structure databases, UniProtKB ( 16 ) reports continued exponential growth of much data, growth made manageable by a focus on Reference Proteomes. There is an interesting discussion of the importance of primary manual curation of the Swiss-Prot portion of the database, especially in cases that computational methods would struggle with, and mention of new methods that might contribute to better propagation of that information to the unreviewed UniProtKB/TrEMBL section. Some of these methods use domain assignments from InterPro ( 17 ), also contributing an update here describing, among other improvements, annotation with ‘flavors’ of intrinsic disorder and better treatment of discontinuous domains. A contributor to InterPro and major resource in its own right Pfam also has an update paper ( 18 ). It reports refinement of many existing entries and the generation of over 800 new protein families using the ECOD structural database ( 19 ). This exercise helped refine the description of some Domains of Unknown Function, while the paper also explains how useful annotations for these can flow back from InterPro work to integrate and rationalize content across its multiple contributing databases. For protein structure both the wwPDB consortium ( 20 ) and the RCSB ( 21 ) report updates, the former pointing out the deposition and validation challenges brought by cryo-EM and serial femtosecond crystallography, the latter listing the impressive variety of external resources integrated into the webpages and describing the incorporation of a new method for description of biological assemblies. Protein post-translational modifications are well-covered by the returning PhosphoSitePlus ® database ( 22 ), now 15 years old and with exciting new integration of disease-related mutations and protein isoform data, and the iEKPD resource ( 23 ) for phosphorylation-related protein domains. They are joined by the new database qPhos ( 24 ) covering the dynamics of protein phosphorylation. Among other interesting new arrivals are the Ancestral Genomes database ( 25 ), providing reconstructed proteomes for 78 extinct ancestors of current species and two new resources for transmembrane proteins: EncoMPASS ( 26 ) focusing on structural similarities and symmetries, and MemProtMD ( 27 ) which provides the results of embedding the structures in a lipid bilayer and subsequent coarse-grained dynamics simulations.

A major new arrival in the metabolic and signaling section is the Issue’s first Breakthrough Article. It is increasingly apparent that the gut microbiota and human diet interact in complex ways with human host metabolism to influence health and disease. The Virtual Metabolic Human (VMH) database ( 28 ) is an impressively ambitious resource that seeks to capture that complexity through linking together modules containing genes, reactions and chemical compounds within the human cell (both as a whole and in compartments) and gut microbes (more than 600 species). Further resources cover nutrition, both in terms of typical diets and in mapping dietary components onto VMH metabolites. As well as inter-connectedness between these modules, VMH links out to more than 50 other databases. The authors envisage that simulations employing VMH with different diets and different microbial abundances can be used to generate testable hypotheses, for example, regarding correlations between microbiota composition and disease states.

Elsewhere, two returning manually curated databases focus on protein complexes. CORUM ( 29 ) covers mammalian complexes and new features include a network-style visualization of subunit interactions and, most interestingly, a recognition and accounting of the impact alternative splicing can have on protein complex function. Complex Portal ( 30 ) presents a new interface incorporating visualizations of data from other databases on metabolism, protein structure and gene expression. The very popular database of protein–protein functional associations STRING reports ( 31 ) an update to version 11.0. Not only has the number of species covered doubled since the previous version, but the database now allows genome-scale expression dataset uploads and annotation of the resulting networks according to gene-set enrichment analysis. The well-used HumanNet ( 32 ), comprising a network of human gene associations with data weighted in a Bayesian framework, reports an update. Already employed data such as protein–protein interactions increased significantly in volume and were supplemented by two novel sources of data, pathway annotations and co-essentiality data. New candidates for involvement in disease can be identified by network-based expansion from a set of known guide genes. Finally, the KEGG database, particularly valued for its pathway reconstructions, reports important new developments in the shape of the KEGG NETWORK and KEGG VARIANT components ( 33 ). These human-specific elements allow the integration of variants such as cancer-related mutations of signaling proteins into networks (derived from KEGG’s original pathways) in order to visualize the effects of perturbation on disease-related pathways. A network variation map summarizes the impacts of a set of perturbants—which may also include viral proteins, environmental factors and drugs—on a given pathway.

The microbial genomics section contains updates from twin Joint Genome Institute databases. The IMG/M database of genomes, metagenomes and metatranscriptomes reports growth of around 60% in just 2 years ( 34 ). Its interface is improved in a variety of ways, including a powerful new search capability, BLAST searches against specific and bespoke databases, and powerful statistical comparisons of gene function between groups. IMG/M links to genomic metadata in the longstanding GOLD database, also reporting an update here ( 35 ). The IMG/VR viral genomics resource has tripled in size in the same period and now includes improved viral host prediction and geographic mapping for uncultivated viral genomes ( 36 ). Two virulence factor (VF) databases are included this year. The first, the well-established VFDB ( 37 ) reports a new automated tool, VFanalyzer, for the identification of VFs in complete or draft bacterial genomes. It combines sequence similarity searches with a consideration of genomic context to achieve performance that is reportedly comparable with human curation. The new Victors database ( 38 ) has manually curated information from over 5000 VFs and a broader scope—encompassing bacterial, viral, parasitic and fungal VFs—than comparable resources.

Human and model organism genomics again has a strong presence, starting with the second of the Issue’s Breakthrough Articles. Vibrism DB ( 39 ) contains anatomical, gene expression and co-expression data at different ages of the mouse brain presenting the information in ways including interactive 3D visualization in a browser. More than 170 000 individual expression maps covering coding and non-coding transcripts are included and co-expression can be viewed in anatomical context or in a network format. The database covers many more transcripts than similar resources, requires few brains to profile expression and cleverly allows users to share URLs that encode scene-setting parameters enabling easy sharing of visualizations. Elsewhere in the section, the major resources Ensembl ( 40 ) and the UCSC Genome Browser ( 41 ) present their usual updates and are joined by GENCODE ( 42 ). A new arrival, the Trips-Viz transcriptome browser ( 43 ) allows for mapping of Ribo-Seq and mRNA-seq data onto individual transcripts from seven model organisms. Popular model organism databases such as FlyBase ( 44 ), ZFIN ( 45 ) and PlanMine ( 46 ) are joined by the new resource iDOG ( 47 ) which contains an impressive variety of data relating to domestic dogs and other canids, and which is designed to appeal to interested lay people as well as expert researchers. The ArrayExpress functional genomics database marks 15 years since its first appearance in this journal with an update ( 48 ) reporting the increasing proportion of submissions coming from single cell studies and the challenges of capturing appropriate metadata.

A large number of databases in the areas of human genomic variation, diseases and drugs are included in this Issue. The popular returning database GWAS Catalog ( 49 ) now includes studies from over 3500 publications, while a pair of new databases—EWAS Atlas ( 50 ) and EWASdb ( 51 )—each service the fast-growing area of Epigenome-Wide Association Studies. The new database PopHumanScan ( 52 ) processes population genomics data from last year’s PopHuman database ( 53 ) revealing almost 3000 candidate human genome regions under positive selection. They are linked to relevant literature in the database while users are also invited to contribute their own candidate regions for curation. CADD ( 54 ) is a major new arrival and is a very popular measure for predicting the deleteriousness of genome variants. Its classification model is trained using a large number of features, including protein, genome and epigenome information. The deleteriousness of both single nucleotide variants and short insertions or deletions can be predicted. A new database, AWESOME ( 55 ), specifically addresses the impact of single nucleotide variants on protein post-translational modifications, considering the effects of around 1 million variants from dbSNP ( 56 ) on six different modifications. The venerable OMIM database, linking genes and phenotypes such as inherited disorders, reports continued strong growth of around 300 new phenotypes per year such that over 6000 phenotypes are now linked to around 4000 genes ( 57 ). Several cancer databases are covered, including the popular curated catalogue of cancer mutations COSMIC ( 58 ). The 3D protein structural consequences of cancer-related mutations are covered in COSMIC-3D and in the dedicated resource Cancer3D ( 59 ). The roles of long non-coding RNAs in cancer are the subject of the returning database Lnc2Cancer ( 60 ), while disease in general is covered by the similarly popular and hugely expanded LncRNADisease ( 61 ). In vivo study of cancers will be facilitated by the new Cell Model Passports database ( 62 ) which contains standardized information for over 1200 cell models enabling a rational choice of cell model for a particular purpose to be made.

Plant databases include the return of the Genome Database for Rosaceae, celebrating 15 years ( 63 ), and the new arrival of the Cucurbit Genomics Database ( 64 ), covering important crops such as pumpkin, melon and cucumber. Another new arrival, CMAUP ( 65 ), aims to catalogue the chemical compounds present in plants of different kinds (edible, medicinal, garden etc.) and distributions, linking them to effects on human proteins, pathways and diseases. It includes over 5000 plants and almost 50 000 ingredients. Two important glycobiology databases are included in the last section. The returning glycosciences.DB ( 66 ) reports a new interface and new search options, including the ability to search with glycan (sub-)structures. The newcomer UniLectin3D ( 67 ) contains structural information on lectins, their ligands and their interactions. It features a wide range of visualization options and ample links out to related resources. This section also contains two major proteomics databases: iProX ( 68 ), a new Chinese contributor to the ProteomeXchange consortium and jPOSTdb ( 69 ). Following on from jPOSTrepo, also published in the Database Issue ( 70 ), jPOSTdb subjects the original raw data to a standardized protocol. Post-translational modifications and protein isoforms can be visualized with further options allowing differential expression analysis and protein set enrichment with respect to KEGG pathways and Gene Ontology terms. Finally, it is always a pleasure to welcome databases addressing entirely new kinds of data. Such is the case of AleDB ( 71 ) which records the results of Adaptive Laboratory Evolution experiments whereby microbes are grown in defined conditions and the mutations responsible for improved phenotypes are tracked.

NAR ONLINE MOLECULAR BIOLOGY DATABASE COLLECTION

With the 26th release of the NAR online Molecular Biology Database Collection (which is freely available at http://www.oxfordjournals.org/nar/database/c ), we feature 66 new resources. We continue to monitor the collection to ensure the information is still relevant and resources are running, contacting authors when repeated downtime is detected. Thanks to this verification process we have updated 506 database entries, removing 147 obsolete or discontinued databases.

We are happy to include new databases in the Collection and we encourage authors of resources published elsewhere to contact us. Such suggestions should be addressed to XMF at [email protected] and should include database summaries in plain text, organized in accordance with the http://www.oxfordjournals.org/nar/database/summary/1 template.

ACKNOWLEDGEMENTS

We thank Dr Martine Bernardes-Silva, especially, and the rest of the Oxford University Press team led by Joanna Ventikos and Elisabeth Waelkens for their help in compiling this issue.

Funding for open access charge: Oxford University Press.

Conflict of interest statement . The authors’ opinions do not necessarily reflect the views of their respective institutions.

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AGGRESCAN3D (A3D): server for prediction of aggregation properties of protein structures

Affiliations.

• 1 Institut de Biotecnologia i Biomedicina and Departament de Bioquímica i Biologia Molecular, Universitat Autònoma de Barcelona, Bellaterra, 08193, Spain.
• 2 University of Warsaw, Faculty of Chemistry, Pasteura 1, Warsaw, Poland.
• 3 University of Warsaw, Faculty of Chemistry, Pasteura 1, Warsaw, Poland [email protected].
• 4 Institut de Biotecnologia i Biomedicina and Departament de Bioquímica i Biologia Molecular, Universitat Autònoma de Barcelona, Bellaterra, 08193, Spain [email protected].
• PMID: 25883144
• PMCID: PMC4489226
• DOI: 10.1093/nar/gkv359

Protein aggregation underlies an increasing number of disorders and constitutes a major bottleneck in the development of therapeutic proteins. Our present understanding on the molecular determinants of protein aggregation has crystalized in a series of predictive algorithms to identify aggregation-prone sites. A majority of these methods rely only on sequence. Therefore, they find difficulties to predict the aggregation properties of folded globular proteins, where aggregation-prone sites are often not contiguous in sequence or buried inside the native structure. The AGGRESCAN3D (A3D) server overcomes these limitations by taking into account the protein structure and the experimental aggregation propensity scale from the well-established AGGRESCAN method. Using the A3D server, the identified aggregation-prone residues can be virtually mutated to design variants with increased solubility, or to test the impact of pathogenic mutations. Additionally, A3D server enables to take into account the dynamic fluctuations of protein structure in solution, which may influence aggregation propensity. This is possible in A3D Dynamic Mode that exploits the CABS-flex approach for the fast simulations of flexibility of globular proteins. The A3D server can be accessed at http://biocomp.chem.uw.edu.pl/A3D/.

© The Author(s) 2015. Published by Oxford University Press on behalf of Nucleic Acids Research.

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( a ) The aggregation…

( a ) The aggregation propensity of myoglobin (PDB: 4MBN) is analyzed using…

A3D analysis of the β-chains…

A3D analysis of the β-chains of deoxyhemoglobin S (PDB: 2HBS:D) (left) and deoxyhemoglobin…

WT β2-m (PDB: 2D4F) and…

WT β2-m (PDB: 2D4F) and variants ΔN6, I7A were modeled and analyzed A3D…

Example output interfaces for WT…

Example output interfaces for WT β2m (PDB: 2D4F). The output is organized under…

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All articles published in NAR are made freely available online immediately upon publication, under an Open Access model partially funded by author charges. Please visit the Open Access Initiative page for more information. The NAR Web Server Issue is published online only, and no print copies are available for purchase.

Nucleic Acids Research devotes a single issue in July to papers describing web-based software resources of value to the biological community. The Web Server Issue contains papers describing software programs that run on the web and provide useful computations on DNA, RNA and protein sequences or structures; analysis of high throughput sequencing data and microarray data; metagenomic and microbiome analysis, network and pathway analysis; biological text mining; tools for synthetic biology; and innovative visualizations. In addition, there is a special section for Web Services. This category includes short papers describing websites that implement useful web services, i.e. automated analyses that are accessed programmatically rather than through manual interaction with a web server.

Stand-Alone applications for high-throughput data analysis are no longer covered by the Web Server Issue , please submit them as Standard articles to the ‘Computational Biology’ section.

Web Servers must:

• be functional on the date of the proposal submission. Access to the server must be through a web browser.
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• include a simple mechanism to try out sample data provided by the authors, for example, a button for automatic loading of the data. Sample data must be accessible to users so that they can confirm data formatting requirements.
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Websites that use a guest login will not be approved.

Web Services must:

• provide a help page which contains a comprehensive list of the web services available along with a clear description and the access URL of each.
• provide a template script in python or another commonly used programming language, that can be run to access several of the web services and parse the output data. The goal is to give the user (and the reviewers) a working template for web services access. Ideally, the program should be easily modifiable so that it can be used for all the web services available.
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Web Servers that handle sensitive human data (e.g. health records or genetic data) may require registration and login. In these cases, users must be able to register themselves without providing their email address. Registration must be handled automatically by the website. Access to non-human data must be possible without registration.

Authors wishing to submit manuscripts for the Web Server Issue MUST read and follow these instructions. See also the editorial from the 2017 issue and the NAR policy on software availability .

Authors must upload a one-page summary at http://nar.bihealth.de/  to check the suitability of their proposed submission by 20 December  at the latest. Proposals sent in before 1 0 November  will not be reviewed until after that date.

Proposals that are discouraged :

• Servers that primarily aggregate data from several sources or assemble together existing third-party tools.
• Servers that employ third-party software that has more restrictive usage terms than the "free and open to all…" statement.
• Analysers of large data files, such as high-throughput sequencing data files.
• Servers that produce primarily downloadable files without corresponding data visualisation in the browser.
• Yes/No decision predictors, multi-state classifiers, or producers of numerical scores meant to inform classification, that lack additional useful supporting information or further analysis.
• Web servers using new methods that have not been previously validated in a separate peer-reviewed publication or that have been published for less than a year.
• New predictors based on machine learning unless the predictors have been validated in a separate peer-reviewed publication.

Note that servers that provide an interface into a single database will not normally be considered for this issue, but instead should be described as part of an article devoted to the database and submitted for consideration in the annual Database Issue .

For web servers, or essentially similar web servers, that have been the subject of a previous publication, including publication in journals other than NAR, there is a minimum two-year interval before re-publication in the Web Server Issue.

The ONE PAGE SUMMARY MUST :

• contain, at the top, one of the following affirmative statements:
• "This website is free and open to all users and there is no login requirement."
• "This website is free and open to all users. Upload and analysis of sensitive personal information requires a login."
• provide descriptions of the input data, the output, and the processing method; complete citations for previous publications of the method or the web server; and two to four keywords.
• include a notification if this is an update from a previous publication in the Web Server issue or elsewhere, and in that case, include an estimate of the number of users and the number of citations.
• include a notification if this is a resubmission of a proposal or a paper rejected in a previous year.

Additionally, any third-party software employed by the website that has more restrictive usage terms must be listed.

On the upload page, the following must be specified:

• website address.
• website name.
• names, affiliations, and email addresses of all authors.
• the Pubmed ID(s) of peer-reviewed manuscripts that describe the method (if applicable).
• the browsers and/or operating systems under which the software was tested.

Free access to the website will be checked during submission.

IF THE WEB SERVER IS PREDICTIVE , authors MUST include, within the summary, details on validation of predictions from new data not used in training. N-fold cross validation studies will not be considered sufficient. Details should include size and composition of the validation data set (number of positive and negative cases), and several measures of predictive performance, including sensitivity, specificity, and precision.

IF THE WEBSITE IMPLEMENTS A META-SERVER OR COMPUTATIONAL WORKFLOW , the summary MUST describe 1) significant added value beyond the simple chaining together of existing third party software or the calculation of a consensus prediction from third party predictors and classifiers; and at least one of the following: 2) how user time for data gathering and multi-step analysis is significantly reduced, or 3) how the website offers significantly enhanced display of the data and results.

IF THE WEB SERVER DEALS WITH PROTEIN STRUCTURE TOPICS , the summary MUST report performance on recent CASP experiments.

IF THE WEB SERVER DEALS WITH PROTEIN OR PEPTIDE DOCKING , the summary MUST report performance on recent CAPRI experiments.

IF THE WEB SERVER DEALS WITH PROTEIN FUNCTION PREDICTION , the summary MUST report performance on recent CAFA experiments

It is expected that the website will be maintained for at least five years .

Authors should restrict themselves to a maximum of three proposals .

Manuscripts

For proposals given approval, the manuscript submission deadline will be 3 weeks after the date of the approval email or 31 January, whichever is later. (Authors are encouraged to be patient. Proposal reviews take up most of January.) Manuscripts will undergo an initial round of editorial review before being sent to reviewers and may be rejected at that time if they are determined to be inappropriate for the journal. The deadlines for revision of manuscripts are tight, typically only two or three weeks are allowed.

• The manuscript MUST contain one of the following affirmative statements:
• "This website is free and open to all users. Upload and analysis of sensitive personal information requires a login."  
• Authors should submit their manuscript electronically through ScholarOne Manuscripts . In case of difficulty, queries should be addressed to  [email protected] .
• All submissions to NAR must include at least one named author, who will serve as the corresponding author. If a paper was authored by a collaborator group, one author must be chosen as the corresponding author and will be listed as the author "on behalf of" the collaborator group
• Authors are encouraged to use the NAR Word and LaTeX  templates. The manuscript text (including references, figure legends and simple tables) may be in .pdf, .doc, .rtf, or LaTeX format. For the initial submission a .pdf file is acceptable.
• In the submission form box titled Key Points, include up to three short sentences (bullet points) briefly describing the key features of the submission.
• As an additional file, include a graphical abstract (this is due only with the first manuscript revision, but may be included with the original manuscript). Follow this link for guidelines for graphical abstracts .
• At the time of manuscript submission authors MUST include a cover letter listing other websites that do similar or identical computations, along with their URLs.
• Authors must supply the names, institutes, and email addresses of six suggested referees. They should be scientists working independently (i.e. not a recent collaborator) who have relevant expertise or who would be likely users of the web server.
• Authors should try to use the name(s) of the software as the first word(s) in the title of the article and should include within the abstract a valid URL from which the software can be accessed. NAR is available in full-text form on the web , and each article will contain a link to its web server URL.
• The manuscript should include a description of the software including the required input, the range of computations it can perform, and examples of the output returned to the user. Comparison with existing methods should also be included. One or more use case studies should be presented to illustrate how the website can provide new biological insights. Submissions should typically be 4-5 printed journal pages in length, but authors are urged to be succinct in their writing, given the tight page constraints of this special issue.
• Manuscripts that contain only a cursory description of the web server and are instead mainly devoted to use of the server for some particular data analyses are not appropriate.
• Manuscripts that provide a first description of a new algorithmic method are generally inappropriate for the Web Server issue and should be submitted instead for consideration as a Computational Biology Standard paper.
• Authors should submit supplementary data if appropriate. Such material could include a description of the mathematics behind an algorithm used by the web server or a tutorial describing how the software should be used if it is non-intuitive. All supplementary data must be available at the time of submission, for editorial review, and the final material will be archived on the NAR web site.
• The software must be completely functional and have been extensively tested at the time of submission . Reviewers should not be expected to debug the software and significant problems that should have been picked up during testing will be grounds for rejection.
• References must be in the correct journal format and should be cited in the text by sequential number only, in order of appearance, and listed numerically in the References section. Manuscripts 'submitted' or 'in preparation', URLs, and personal communications should not be cited. Please note that references include the full titles of each paper. For more specific information, please consult the NAR web site .
• The references section must include active electronic DOI and PubMed Central links for each cited paper (where available). Please include a PubMed abstract link if the PMC link is not available. Programs to help insert the links into the references section are available.
• The home page for the software should not be used as a figure in the article unless an explanation of the page is required. A more appropriate figure would include the result of a typical computation.
• Authors whose native language is not English are encouraged to ask a native English speaker to check the text prior to submission. Follow this link for a list of English language service providers .
• For more specific information, please consult the general Instructions to Authors .

To help authors evaluate their manuscripts, the instructions to reviewers are included below:

When reviewing papers for the NAR Web Server Issue, please be aware of the following points:

• The purpose of this software issue is to provide a single location where potential users of web-based software can find out what is available and what the software actually does.
• While originality is not necessarily an issue, if software with similar functionality is available from other sources, then there must be something significant and new in this contribution. Comparison to existing methods should be included in the manuscript.
• A key consideration on acceptability will be whether the software described in the manuscript is useful and whether it works over the web as described. It is important that the package be tested thoroughly, preferably on at least two commonly used web browsers to make sure that it works as advertised and has an interface that is user-friendly.
• The software should provide analysis of wide interest. A program that is relevant to only a few individuals is unlikely to make it into the issue.
• Some web servers are predictive. In this case the manuscript must provide evidence of validation independent of any training data. Details should include size and composition of the validation data set (number of positive and negative cases), and several measures of predictive performance, such as sensitivity, specificity, precision, and any others that are appropriate.
• Some web servers are meta-servers or computational pipelines. In this case, the manuscript must describe 1) significant added value beyond the simple chaining together of existing third party software or the calculation of a consensus prediction from third party predictors and classifiers; and at least one of the following: 2) how user time for data gathering and multi-step analysis is significantly reduced or 3) how the website offers significantly enhanced display of the data and results.
• Some web servers deal with protein structure topics. In this case, the manuscript must report performance on recent relevant CASP experiments.
• Some web servers deal with protein and peptide docking. In this case, the manuscript must report performance on recent relevant CAPRI experiments.
• Some web servers deal with protein function prediction. In this case, the manuscript must report performance on recent relevant CAFA experiments.
• The software may have been described in an earlier publication. In this case, the paper should include the appropriate reference(s) and should contain a description of what is new and different. In such cases, brevity is essential.
• The author has stated that the website is free and open to all and that there is no login requirement (unless sensitive data is transmitted). Guest login must not be required. Additionally, while the website may request an email address, the address must be optional and not be required to obtain results. Please notify me in your review if this is not the case.
• Constructive comments that will lead to an improved manuscript or an improved piece of software on the web will be the most helpful. Most manuscripts describing a server that is significantly different from anything else available will be acceptable eventually, unless the piece of software does not work, gives erroneous results, or is simply of no practical use.

The Web Server Issue receives several hundred proposals and manuscripts. Due to the crush around deadlines, authors should be patient about responses from the editor. Reply to proposals will typically be made by mid-February. Reviews of manuscripts should be received by mid-April.

For further information please contact Dr. Dominik Seelow at [email protected] .

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