Jyoti Khadake

IntAct—open source resource for molecular interaction data

IntAct is an open source database and software suite for modeling, storing and analyzing molecular interaction data. The data available in the database originates entirely from published literature and is manually annotated by expert biologists to a high level of detail, including experimental methods, conditions and interacting domains. The database features over 126 000 binary interactions extracted from over 2100 scientific publications and makes extensive use of controlled vocabularies. The web site provides tools allowing users to search, visualize and download data from the repository. IntAct supports and encourages local installations as well as direct data submission and curation collaborations. IntAct source code and data are freely available from .

The MIntAct project—IntAct as a common curation platform for 11 molecular interaction databases

IntAct (freely available at http://www.ebi.ac.uk/intact) is an open-source, open data molecular interaction database populated by data either curated from the literature or from direct data depositions. IntAct has developed a sophisticated web-based curation tool, capable of supporting both IMEx- and MIMIx-level curation. This tool is now utilized by multiple additional curation teams, all of whom annotate data directly into the IntAct database. Members of the IntAct team supply appropriate levels of training, perform quality control on entries and take responsibility for long-term data maintenance. Recently, the MINT and IntAct databases decided to merge their separate efforts to make optimal use of limited developer resources and maximize the curation output. All data manually curated by the MINT curators have been moved into the IntAct database at EMBL-EBI and are merged with the existing IntAct dataset. Both IntAct and MINT are active contributors to the IMEx consortium (http://www.imexconsortium.org).

Protein interaction data curation: the International Molecular Exchange (IMEx) consortium

The International Molecular Exchange (IMEx) consortium is an international collaboration between major public interaction data providers to share literature-curation efforts and make a nonredundant set of protein interactions available in a single search interface on a common website (http://www.imexconsortium.org/). Common curation rules have been developed, and a central registry is used to manage the selection of articles to enter into the dataset. We discuss the advantages of such a service to the user, our quality-control measures and our data-distribution practices.

PSICQUIC and PSISCORE: accessing and scoring molecular interactions

To study proteins in the context of a cellular system, it is essential that the molecules with which a protein interacts are identified and the functional consequence of each interaction is understood. A plethora of resources now exist to capture molecular interaction data from the many laboratories generating…

Recurated protein interaction datasets

controlled vocabularies for annotation allows the database users to efficiently select subsets of data according to criteria relevant for their particular use. In contrast, Cusick et al.1 define a set of criteria for a specific use restricted only to direct pairwise protein-protein interactions, which they refer to as ‘binary’ interactions. They evaluate literature-curated datasets against these criteria and then assert that failure to meet their criteria represents “incorrect curation.” The criteria defined by Cusick et al.1 vary slightly from species to species but aim to select only direct interactions with multiple independent supporting reports. While this is one valid use, other users might, for example, look for all observed interactions of a given protein, whether direct or indirect, to subsequently assess the supporting evidence by reading the supporting publications. Whereas protein-protein interaction databases may also use the term ‘binary’ when referring to pairs of interacting proteins, our usage of the term refers to any interaction pair and makes no judgment regarding whether the interaction is direct or indirect. We strongly object to the notion that inclusion of an interaction with limited supporting evidence of a direct interaction represents a curation error. On the contrary, most interaction databases always fully curate a given publication and would consider it an egregious omission if only a subset of the protein interactions reported in a publication or its supplementary material would be contained in the database. When informationfor example, species informationin a publication is ambiguous, database curators attempt to contact the authors and only leave out data if clarification cannot be obtained. In response to the claims of Cusick et al.1, we reanalyzed interactions presented in their paper to identify actual curation errors, defined as inconsistencies between the original published data and their representation in our databases. Details of our analysis are available in the Supplementary Note, and we reannotated versions of the original tables supplied by Cusick et al.1 (Supplementary Tables 1–3). The actual curation error rate was, in fact, consistently under 10%. For the yeast dataset, we confirmed 4 actual curation errors among the 100 sample interactions from BioGRID chosen by Cusick et al.1; the curation error rate of 4% is precisely the value originally reported for the dataset7 and an order of magnitude lower than the claim by Cusick et al.1: “Of the interacting pairs in the sample, 35% were incorrectly curated.” For comparison, we analyzed a subset of the BioGRID data that is also present in the DIP database and identified 1 actual curation error out of 29 shared records, that is, a similarly low error rate of 3%. For the human dataset, of the 220 sampled interactions annotated in MINT, only 10 were curation errors, corresponding to a curation error rate of 4.5%. Similarly, only 4 out of 42 curation records reported in DIP contained errors, a 9% curation error rate, or one-fifth of the 45% curation error rate implied by Cusick et al.1. For the Arabidopsis thaliana, the IntAct dataset contained 3 actual curation errors in 183 curation records, resulting in an error rate of 2%, less than one-fifth of the 10.7% rate claimed by Cusick et al.1 in their Table 2. For TAIR, the actual error rate was only 3%, or less than one-third of the rate claimed by Cusick et al.1. Accurate and detailed curation is an arduous process both in terms of individual curator expertise and curation time. To optimize the use of public funding, the member databases of the International Molecular Exchange Consortium (IMEx)8 DIP, IntAct and MINT coordinate their curation efforts to avoid unnecessary redundancy, measured in PBS4, which may result in an overestimation of photostability compared to commonly used live-cell imaging conditions. The use of media depleted of vitamins for fluorescence imaging of live cultured cells appears to be a simple and efficient way to improve the performance of some widely used fluorescent proteins in various ensemble and single-molecule applications1,5,6.

MINT and IntAct contribute to the Second BioCreative challenge: serving the text-mining community with high quality molecular interaction data

BackgroundIn the absence of consolidated pipelines to archive biological data electronically, information dispersed in the literature must be captured by manual annotation. Unfortunately, manual annotation is time consuming and the coverage of published interaction data is therefore far from complete. The use of text-mining tools to identify relevant publications and to assist in the initial information extraction could help to improve the efficiency of the curation process and, as a consequence, the database coverage of data available in the literature. The 2006 BioCreative competition was aimed at evaluating text-mining procedures in comparison with manual annotation of protein-protein interactions.ResultsTo aid the BioCreative protein-protein interaction task, IntAct and MINT (Molecular INTeraction) provided both the training and the test datasets. Data from both databases are comparable because they were curated according to the same standards. During the manual curation process, the major cause of data loss in mining the articles for information was ambiguity in the mapping of the gene names to stable UniProtKB database identifiers. It was also observed that most of the information about interactions was contained only within the full-text of the publication; hence, text mining of protein-protein interaction data will require the analysis of the full-text of the articles and cannot be restricted to the abstract.ConclusionThe development of text-mining tools to extract protein-protein interaction information may increase the literature coverage achieved by manual curation. To support the text-mining community, databases will highlight those sentences within the articles that describe the interactions. These will supply data-miners with a high quality dataset for algorithm development. Furthermore, the dictionary of terms created by the BioCreative competitors could enrich the synonym list of the PSI-MI (Proteomics Standards Initiative-Molecular Interactions) controlled vocabulary, which is used by both databases to annotate their data content.

Genome-wide meta-analysis of cognitive empathy: heritability, and correlates with sex, neuropsychiatric conditions and cognition

We conducted a genome-wide meta-analysis of cognitive empathy using the ‘Reading the Mind in the Eyes’ Test (Eyes Test) in 88,056 research volunteers of European Ancestry (44,574 females and 43,482 males) from 23andMe Inc., and an additional 1497 research volunteers of European Ancestry (891 females and 606 males) from the Brisbane Longitudinal Twin Study. We confirmed a female advantage on the Eyes Test (Cohen’s d=0.21, P<2.2 × 10−16), and identified a locus in 3p26.1 that is associated with scores on the Eyes Test in females (rs7641347, Pmeta=1.58 × 10−8). Common single nucleotide polymorphisms explained 5.8% (95% CI: 4.5%–7.2%; P=1.00 × 10−17) of the total trait variance in both sexes, and we identified a twin heritability of 28% (95% CI: 13%–42%). Finally, we identified significant genetic correlation between the Eyes Test and anorexia nervosa, openness (NEO-Five Factor Inventory), and different measures of educational attainment and cognitive aptitude.

VRK1 interacts with p53 forming a basal complex that is activated by UV‐induced DNA damage

DNA damage immediate cellular response requires the activation of p53 by kinases. We found that p53 forms a basal stable complex with VRK1, a Ser–Thr kinase that responds to UV‐induced DNA damage by specifically phosphorylating p53. This interaction takes place through the p53 DNA binding domain, and frequent DNA‐contact mutants of p53, such as R273H, R248H or R280K, do not disrupt the complex. UV‐induced DNA damage activates VRK1, and is accompanied by phosphorylation of p53 at Thr‐18 before it accumulates. We propose that the VRK1–p53 basal complex is an early‐warning system for immediate cellular responses to DNA damage.

Regulatory Elements Associated with Paternally-Expressed Genes in the Imprinted Murine Angelman/Prader-Willi Syndrome Domain

The Angelman/Prader-Willi syndrome (AS/PWS) domain contains at least 8 imprinted genes regulated by a bipartite imprinting center (IC) associated with the SNRPN gene. One component of the IC, the PWS-IC, governs the paternal epigenotype and expression of paternal genes. The mechanisms by which imprinting and expression of paternal genes within the AS/PWS domain – such as MKRN3 and NDN – are regulated by the PWS-IC are unclear. The syntenic region in the mouse is organized and imprinted similarly to the human domain with the murine PWS-IC defined by a 6 kb interval within the Snrpn locus that includes the promoter. To identify regulatory elements that may mediate PWS-IC function, we mapped the location and allele-specificity of DNase I hypersensitive (DH) sites within the PWS-IC in brain cells, then identified transcription factor binding sites within a subset of these DH sites. Six major paternal-specific DH sites were detected in the Snrpn gene, five of which map within the 6 kb PWS-IC. We postulate these five DH sites represent functional components of the murine PWS-IC. Analysis of transcription factor binding within multiple DH sites detected nuclear respiratory factors (NRFs) and YY1 specifically on the paternal allele. NRFs and YY1 were also detected in the paternal promoter region of the murine Mrkn3 and Ndn genes. These results suggest that NRFs and YY1 may facilitate PWS-IC function and coordinately regulate expression of paternal genes. The presence of NRFs also suggests a link between transcriptional regulation within the AS/PWS domain and regulation of respiration. 3C analyses indicated Mkrn3 lies in close proximity to the PWS-IC on the paternal chromosome, evidence that the PWS-IC functions by allele-specific interaction with its distal target genes. This could occur by allele-specific co-localization of the PWS-IC and its target genes to transcription factories containing NRFs and YY1.

Preferential condensation of SAR-DNA by histone H1 and its SPKK containing octapeptide repeat motif

Linker histone H1 binds preferentially the scaffold associated region (SAR) DNA elements that contain characteristic oligo dA·dT tracts. In the present study, we have compared the condensation brought about by histone H1 of a SAR DNA fragment in the histone spacer region of Drosophila melanogaster with that of a random DNA (pBR322 EcoRI‐SalI) fragment by circular dichroism spectroscopy. The condensation of the SAR DNA fragment by histone H1 is 3–4‐fold higher than that of the random DNA fragment. A 16‐mer peptide, ATPKKSTKKTPKKAKK, the sequence that is present in the C‐terminus of histone H1d, which has recently been shown to possess DNA and chromatin condensing properties, also condenses the SAR DNA fragment preferentially in a highly cooperative manner. We have proposed a model for the dynamics of chromatin structure involving histone H1‐SAR DNA interaction through SPKK containing peptide motifs and its competition by AT‐hook peptides present in the nonhistone chromosomal proteins like HMG‐I and HMG‐Y.