Overview of the StoneMod database
The aim of our present work was to build a database that integrates all relevant information of kidney stone modulators with experimental evidence. The StoneMod database provides a collection of modulatory proteins that either promote or inhibit individual steps of kidney stone formation. Using the predefined criteria for inclusion/exclusion (Fig. 2) (see more details in “Materials and Methods”), the StoneMod database currently contains 10, 16, 13, 8 modulatory proteins that affect calcium oxalate crystallization, crystal growth, crystal aggregation, and crystal adhesion on renal tubular cells, respectively (Table 1). All of these data were retrieved from 62 published studies, involving urine, serum, cellular secretome, and kidney tissue samples (Supplementary Table S1). Informative details of each modulatory protein and PubMed links to the published articles are provided. Additionally, hyperlinks to other protein/gene databases (i.e., UniProtKB, Swiss-Prot, Human Protein Atlas, PeptideAtlas, and Ensembl) are made available for the users to obtain additional in-depth information of each protein.
The tabbed document interface
The StoneMod database website is an open access resource for obtaining detailed information of kidney stone modulatory proteins that has been designed and organized for the ease of use and access. Using the MySQL schema as detailed in “Materials & Methods” (Fig. 3), the website tabbed document interfaces at this initial phase include “home”, “about us”, “lists”, “advanced search”, “data submission”, “contact”, and “help” tabs (Fig. 4A). The home page provides an overview of the database, brief background of kidney stone formation, and news of the database or related issues (Fig. 4A). This page also shows three most updated modulatory proteins and their modulatory activities.
The lists menu provides two choices, in which modulators are sorted by alphabetical order or by activity involving crystallization, crystal growth, crystal aggregation, or crystal adhesion on renal tubular cells (Figs. 4B,C). For each step of kidney stone formation, individual modulatory proteins are categorized by their modulatory effects (e.g., promotion or inhibition). Quick search can be done through the home page using generalized keyword (e.g. protein common name, protein alternative name, gene name, gene symbol, UniProtKB accession number, etc.) (Fig. 4D). This allows the users to directly access the information of the protein or modulator of interest. In addition to the quick search, the users can perform advanced search by inputting specified and multiple search parameters (Fig. 4E). In either case, the search result will show brief information of the resulting modulator, including its StoneMod ID, protein name, UniProt ID, gene name, and gene symbol (Fig. 4F). Clicking the protein name will lead the users to the detailed information of each modulatory protein (Fig. 5).
Relevant information of each modulatory protein
The detailed information page includes relevant data of each modulatory protein, including: (i) protein information; (ii) gene information; and (iii) modulatory effects (Table 2). The protein information (retrieved mainly from the UniProtKB database) includes protein common name, alternative name, UniProt ID, protein isoform (if any), and hyperlinks to the proteomic databases (i.e., Human Protein Atlas and PeptideAtlas) (Fig. 5; panel (i)). The gene information (retrieved mainly from the NCBI Gene database) provides gene name, gene symbol, and hyperlink to the gene annotation database (i.e., Ensembl) (Fig. 5; panel (ii)). Details of modulatory effects of each modulator (retrieved mainly from the PubMed search) include all relevant references of its promoting or inhibitory effect on crystallization, crystal growth, crystal aggregation, or crystal adhesion (Fig. 5; panel (iii)). Number of the references in each category is also summarized and shown on this page. Each reference is further linked to the PubMed literature resource. Finally, the StoneMod database also offers the users to download or export all the detailed information as comma-separated values (csv) file format by clicking “export to csv” icon at the bottom of the detailed information page (Fig. 5; panel (iv)).
Some of the modulators had contradictory results shown by different studies (mostly due to differential settings/parameters tested). They are then listed within “contradictory” category in the “lists by activity” tab. For example, there are three modulators (albumin, osteopontin, and uromodulin) that are in the “contradictory” category for crystal growth (Fig. 4C). The detailed information page of each protein will show all the contradictory data in one place (as in the case for albumin in Fig. 5; panel (iii), in which “modulatory effects” section shows all references for inhibitory and promoting effects of albumin on crystal growth.
Data submission and update
In addition to periodic (monthly) deposition and update by our team, the StoneMod database also provides a submission form on “data submission” tab (Fig. 4A) to allow the users to directly deposit or update their own information into the database manually (note that the users must provide the PubMed ID or digital object identifier (DOI) of the published articles). After submission, each filled form will be directly sent to us for review. If the submitted references are relevant and show experimental evidence of modulatory effects of their proteins on kidney stone formation, they will be deposited and updated on the website within a week after submission. Finally, the latest deposited modulator will be highlighted on the home page and the submitter will be credited and notified.