STITCH: interaction networks of chemicals and proteins

The knowledge about interactions between proteins and small molecules is essential for the understanding of molecular and cellular functions. However, information on such interactions is widely dispersed across numerous databases and the literature. To facilitate access to this data, STITCH (‘search tool for interactions of chemicals') integrates information about interactions from metabolic pathways, crystal structures, binding experiments and drug-target relationships. Inferred information from phenotypic effects, text mining and chemical structure similarity is used to predict relations between chemicals. STITCH further allows exploring the network of chemical relations, also in the context of associated binding proteins. Each proposed interaction can be traced back to the original data sources. Our database contains interaction information for over 68 000 different chemicals, including 2200 drugs, and connects them to 1.5 million genes across 373 genomes and their interactions contained in the STRING database. STITCH is available at http://stitch.embl.d

SuperTarget and Matador: resources for exploring drug-target relationships

The molecular basis of drug action is often not well understood. This is partly because the very abundant and diverse information generated in the past decades on drugs is hidden in millions of medical articles or textbooks. Therefore, we developed a one-stop data warehouse, SuperTarget that integrates drug-related information about medical indication areas, adverse drug effects, drug metabolization, pathways and Gene Ontology terms of the target proteins. An easy-to-use query interface enables the user to pose complex queries, for example to find drugs that target a certain pathway, interacting drugs that are metabolized by the same cytochrome P450 or drugs that target the same protein but are metabolized by different enzymes. Furthermore, we provide tools for 2D drug screening and sequence comparison of the targets. The database contains more than 2500 target proteins, which are annotated with about 7300 relations to 1500 drugs; the vast majority of entries have pointers to the respective literature source. A subset of these drugs has been annotated with additional binding information and indirect interactions and is available as a separate resource called Matador. SuperTarget and Matador are available at http://insilico.charite.de/supertarget and http://matador.embl.d

STITCH 2: an interaction network database for small molecules and proteins

Over the last years, the publicly available knowledge on interactions between small molecules and proteins has been steadily increasing. To create a network of interactions, STITCH aims to integrate the data dispersed over the literature and various databases of biological pathways, drug–target relationships and binding affinities. In STITCH 2, the number of relevant interactions is increased by incorporation of BindingDB, PharmGKB and the Comparative Toxicogenomics Database. The resulting network can be explored interactively or used as the basis for large-scale analyses. To facilitate links to other chemical databases, we adopt InChIKeys that allow identification of chemicals with a short, checksum-like string. STITCH 2.0 connects proteins from 630 organisms to over 74 000 different chemicals, including 2200 drugs. STITCH can be accessed at http://stitch.embl.de/

Drug-Induced Regulation of Target Expression

Drug perturbations of human cells lead to complex responses upon target binding. One of the known mechanisms is a (positive or negative) feedback loop that adjusts the expression level of the respective target protein. To quantify this mechanism systems-wide in an unbiased way, drug-induced differential expression of drug target mRNA was examined in three cell lines using the Connectivity Map. To overcome various biases in this valuable resource, we have developed a computational normalization and scoring procedure that is applicable to gene expression recording upon heterogeneous drug treatments. In 1290 drug-target relations, corresponding to 466 drugs acting on 167 drug targets studied, 8% of the targets are subject to regulation at the mRNA level. We confirmed systematically that in particular G-protein coupled receptors, when serving as known targets, are regulated upon drug treatment. We further newly identified drug-induced differential regulation of Lanosterol 14-alpha demethylase, Endoplasmin, DNA topoisomerase 2-alpha and Calmodulin 1. The feedback regulation in these and other targets is likely to be relevant for the success or failure of the molecular intervention

The mediterranean sea we want

open58siThis paper presents major gaps and challenges for implementing the UN Decade of Ocean Science for Sustainable Development (2021-2030) in the Mediterranean region. The authors make recommendations on the scientific knowledge needs and co-design actions identified during two consultations, part of the Decade preparatory-phase, framing them in the Mediterranean Sea’s unique environmental and socio-economic perspectives. According to the ‘Mediterranean State of the Environment and Development Report 2020’ by the United Nations Environment Programme Mediterranean Action Plan and despite notable progress, the Mediterranean region is not on track to achieve and fully implement the Sustainable Development Goals of Agenda 2030. Key factors are the cumulative effect of multiple human-induced pressures that threaten the ecosystem resources and services in the global change scenario. The basin, identified as a climate change vulnerability hotspot, is exposed to pollution and rising impacts of climate change. This affects mainly the coastal zones, at increasing risk of extreme events and their negative effects of unsustainable management of key economic assets. Transitioning to a sustainable blue economy is the key for the marine environment’s health and the nourishment of future generations. This challenging context, offering the opportunity of enhancing the knowledge to define science-based measures as well as narrowing the gaps between the Northen and Southern shores, calls for a joint (re)action. The paper reviews the state of the art of Mediterranean Sea science knowledge, sets of trends, capacity development needs, specific challenges, and recommendations for each Decade’s societal outcome. In the conclusions, the proposal for a Mediterranean regional programme in the framework of the Ocean Decade is addressed. The core objective relies on integrating and improving the existing ocean-knowledge, Ocean Literacy, and ocean observing capacities building on international cooperation to reach the “Mediterranean Sea that we want”.openCappelletto M.; Santoleri R.; Evangelista L.; Galgani F.; Garces E.; Giorgetti A.; Fava F.; Herut B.; Hilmi K.; Kholeif S.; Lorito S.; Sammari C.; Lianos M.C.; Celussi M.; D'alelio D.; Francocci F.; Giorgi G.; Canu D.M.; Organelli E.; Pomaro A.; Sannino G.; Segou M.; Simoncelli S.; Babeyko A.; Barbanti A.; Chang-Seng D.; Cardin V.; Casotti R.; Drago A.; Asmi S.E.; Eparkhina D.; Fichaut M.; Hema T.; Procaccini G.; Santoro F.; Scoullos M.; Solidoro C.; Trincardi F.; Tunesi L.; Umgiesser G.; Zingone A.; Ballerini T.; Chaffai A.; Coppini G.; Gruber S.; Knezevic J.; Leone G.; Penca J.; Pinardi N.; Petihakis G.; Rio M.-H.; Said M.; Siokouros Z.; Srour A.; Snoussi M.; Tintore J.; Vassilopoulou V.; Zavatarelli M.Cappelletto M.; Santoleri R.; Evangelista L.; Galgani F.; Garces E.; Giorgetti A.; Fava F.; Herut B.; Hilmi K.; Kholeif S.; Lorito S.; Sammari C.; Lianos M.C.; Celussi M.; D'alelio D.; Francocci F.; Giorgi G.; Canu D.M.; Organelli E.; Pomaro A.; Sannino G.; Segou M.; Simoncelli S.; Babeyko A.; Barbanti A.; Chang-Seng D.; Cardin V.; Casotti R.; Drago A.; Asmi S.E.; Eparkhina D.; Fichaut M.; Hema T.; Procaccini G.; Santoro F.; Scoullos M.; Solidoro C.; Trincardi F.; Tunesi L.; Umgiesser G.; Zingone A.; Ballerini T.; Chaffai A.; Coppini G.; Gruber S.; Knezevic J.; Leone G.; Penca J.; Pinardi N.; Petihakis G.; Rio M.-H.; Said M.; Siokouros Z.; Srour A.; Snoussi M.; Tintore J.; Vassilopoulou V.; Zavatarelli M

Identification of genetic elements in metabolism by high-throughput mouse phenotyping.

Metabolic diseases are a worldwide problem but the underlying genetic factors and their relevance to metabolic disease remain incompletely understood. Genome-wide research is needed to characterize so-far unannotated mammalian metabolic genes. Here, we generate and analyze metabolic phenotypic data of 2016 knockout mouse strains under the aegis of the International Mouse Phenotyping Consortium (IMPC) and find 974 gene knockouts with strong metabolic phenotypes. 429 of those had no previous link to metabolism and 51 genes remain functionally completely unannotated. We compared human orthologues of these uncharacterized genes in five GWAS consortia and indeed 23 candidate genes are associated with metabolic disease. We further identify common regulatory elements in promoters of candidate genes. As each regulatory element is composed of several transcription factor binding sites, our data reveal an extensive metabolic phenotype-associated network of co-regulated genes. Our systematic mouse phenotype analysis thus paves the way for full functional annotation of the genome

Computational approaches for the study of the role of small molecules in diseases

An enormous amount of molecular and phenotypic information of drugs as well as diseases is now available in public repositories. Computational analysis of these datasets is facilitating the acquisition of a systems view of how drugs act on our human organism and interfere with diseases. Here, I highlight recent approaches integrating large-scale information of drugs and diseases that are contributing to change our current view on how drugs interfere with human diseases