Biology subjects

Domingo-Fernandez, D.

Publications and source records attributed to Domingo-Fernandez, D..

31 records · Page 2Linked to original sources

bioRxiv2020

Unravelling the debate on heme effects in COVID-19 infections

The SARS-CoV-2 outbreak was recently declared a worldwide pandemic. Infection triggers the respiratory tract disease COVID-19, which is accompanied by serious changes of clinical biomarkers such as hemoglobin and interleukins. The same parameters are altered during hemolysis, which is characterized by an increase in labile heme. We present two approaches that aim at analyzing a potential link between available heme and COVID-19 pathogenesis. Four COVID-19 related proteins, i.e. the host cell proteins ACE2 and TMPRSS2 as well as the viral protein 7a and S protein, were identified as potential heme binders. We also performed a detailed analysis of the common pathways induced by heme and SARS-CoV-2 by superimposition of knowledge graphs covering heme biology and COVID-19 pathophysiology. Herein, focus was laid on inflammatory pathways, and distinct biomarkers as the linking elements. Finally, the results substantially improve our understanding of COVID-19 infections and disease progression of patients with different clinical backgrounds and expand the diagnostic and treatment options.

bioinformatics↗

bioRxiv2020

Drug2ways: Reasoning over causal paths in biological networks for drug discovery

Elucidating the causal mechanisms responsible for disease can reveal potential therapeutic targets for pharmacological intervention and, accordingly, guide drug repositioning and discovery. In essence, the topology of a network can reveal the impact a drug candidate may have on a given biological state, leading the way for enhanced disease characterization and the design of advanced therapies. Network-based approaches, in particular, are highly suited for these purposes as they hold the capacity to identify the molecular mechanisms underlying disease. Here, we present drug2ways, a novel methodology that leverages multimodal causal networks for predicting drug candidates. Drug2ways implements an efficient algorithm which reasons over causal paths in large-scale biological networks to propose drug candidates for a given disease. We validate our approach using clinical trial information and demonstrate how drug2ways can be used for multiple applications to identify: i) single-target drug candidates, ii) candidates with polypharmacological properties that can optimize multiple targets, and iii) candidates for combination therapy. Finally, we make drug2ways available to the scientific community as a Python package that enables conducting these applications on multiple standard network formats.

bioinformatics↗

bioRxiv2020

COVID-19 Knowledge Graph: a computable, multi-modal, cause-and-effect knowledge model of COVID-19 pathophysiology

SummaryThe past few weeks have witnessed a worldwide mobilization of the research community in response to the novel coronavirus (COVID-19). This global response has led to a burst of publications on the pathophysiology of the virus, yet without coordinated efforts to organize this knowledge, it can remain hidden away from individual research groups. By extracting and formalizing this knowledge in a structured and computable form, as in the form of a knowledge graph, researchers can readily reason and analyze this information on a much larger scale. Here, we present the COVID-19 Knowledge Graph, an expansive cause-and-effect network constructed from scientific literature on the new coronavirus that aims to provide a comprehensive view of its pathophysiology. To make this resource available to the research community and facilitate its exploration and analysis, we also implemented a web application and released the KG in multiple standard formats. AvailabilityThe COVID-19 Knowledge Graph is publicly available under CC-0 license at https://github.com/covid19kg and https://bikmi.covid19-knowledgespace.de. Contactalpha.tom.kodamullil@scai.fraunhofer.de Supplementary informationSupplementary data are available online.

bioinformatics↗

bioRxiv2019

A computational approach for mapping heme biology in the context of hemolytic disorders

Heme is an iron ion-containing molecule found within hemoproteins such as hemoglobin and cytochromes that participates in diverse biological processes. While its unlimited supply has been implicated in deleterious processes in several diseases including malaria, sepsis, ischemia-reperfusion, and disseminated intravascular coagulation, little is known about its regulatory and signaling functions. A majority of the computational research to elucidate these functions has been purely data-driven due to the absence of curated pathway resources, which have proven useful in the computational study in other indications. Here, we present two resources aimed to exploit this unexplored information to model heme biology. The first resource is an ontology covering heme-specific terms not yet included in standard controlled vocabularies. Using this ontology, we curated and modeled a corpus of 46 scientific articles to generate a mechanistic knowledge graph representing the hemes interactome for that particular literature. Finally, we demonstrated the utility of these resources by investigating the role of heme in the Toll-like receptor signaling pathway. Our analysis proposed a series of crosstalk events that could explain the role of heme in activating the TLR4 signaling pathway. In summary, the presented work opens the door for the scientific community to explore in more detail the published knowledge on heme biology.

bioinformatics↗

bioRxiv2019

The Impact of Pathway Database Choice on Statistical Enrichment Analysis and Predictive Modeling

BackgroundPathway-centric approaches are widely used to interpret and contextualize -omics data. However, databases contain different representations of the same biological pathway, which may lead to different results of statistical enrichment analysis and predictive models in the context of precision medicine.\n\nResultsWe have performed an in-depth benchmarking of the impact of pathway database choice on statistical enrichment analysis and predictive modeling. We analyzed five cancer datasets using three major pathway databases and developed an approach to merge several databases into a single integrative database: MPath. Our results show that equivalent pathways from different databases yield disparate results in statistical enrichment analysis. Moreover, we observed a significant dataset-dependent impact on performance of machine learning models on different prediction tasks. Further, MPath significantly improved prediction performance and reduced the variance of prediction performances in some cases. At the same time, MPath yielded more consistent and biologically plausible results in the statistical enrichment analyses. Finally, we implemented a software package designed to make our comparative analysis with these and additional databases fully reproducible and to facilitate the update of our integrative pathway resource in the future.\n\nConclusionThis benchmarking study demonstrates that pathway database choice can influence the results of statistical enrichment analysis and prediction modeling. Therefore, we recommend the use of multiple pathway databases or the use of integrative databases.

bioinformatics↗

bioRxiv2019

Integration of Structured Biological Data Sources using Biological Expression Language

BackgroundThe integration of heterogeneous, multiscale, and multimodal knowledge and data has become a common prerequisite for joint analysis to unravel the mechanisms and aetiologies of complex diseases. Because of its unique ability to capture this variety, Biological Expression Language (BEL) is well suited to be further used as a platform for semantic integration and harmonization in networks and systems biology.\n\nResultsWe have developed numerous independent packages capable of downloading, structuring, and serializing various biological data sources to BEL. Each Bio2BEL package is implemented in the Python programming language and distributed through GitHub (https://github.com/bio2bel) and PyPI.\n\nConclusionsThe philosophy of Bio2BEL encourages reproducibility, accessibility, and democratization of biological databases. We present several applications of Bio2BEL packages including their ability to support the curation of pathway mappings, integration of pathway databases, and machine learning applications.\n\nTweetA suite of independent Python packages for downloading, parsing, warehousing, and converting multi-modal and multi-scale biological databases to Biological Expression Language

bioinformatics↗

bioRxiv2019

PTSD Biomarker Database: Deep Dive Meta-database for PTSD Biomarkers, Visualizations, and Analysis Tools

The PTSD Biomarker Database (PTSDDB) is a database that provides a landscape view of physiological markers being studied as putative biomarkers in the current post-traumatic stress disorder (PTSD) literature to enable researchers to quickly explore and compare findings. The PTSDDB currently contains over 900 biomarkers and their relevant information from 109 original articles published from 1997 to 2017. Further, the curated content stored in this database is complemented by a web application consisting of multiple interactive visualizations that enable the investigation of biomarker knowledge in PTSD (e.g., clinical study metadata, biomarker findings, experimental methods, etc.) by compiling results from biomarker studies to visualize the level of evidence for single biomarkers and across functional categories. This resource is the first attempt, to the best of our knowledge, to capture and organize biomarker and metadata in the area of PTSD for storage in a comprehensive database that may, in turn, facilitate future analysis and research in the field. Database URLhttps://ptsd.scai.fraunhofer.de

bioinformatics↗

bioRxiv2019

Re-curation and Rational Enrichment of Knowledge Graphs in Biological Expression Language

The rapid accumulation of new biomedical literature not only causes curated knowledge graphs to become outdated and incomplete, but also makes manual curation an impractical and unsustainable solution. Automated or semi-automated workflows are necessary to assist in prioritizing and curating the literature to update and enrich knowledge graphs. We have developed two workflows: one for re-curating a given knowledge graph to assure its syntactic and semantic quality and another for rationally enriching it by manually revising automatically extracted relations for nodes with low information density. We applied these workflows to the knowledge graphs encoded in Biological Expression Language from the NeuroMMSig database using content that was pre-extracted from MEDLINE abstracts and PubMed Central full text articles using text mining output integrated by INDRA. We have made this workflow freely available at https://github.com/bel-enrichment/bel-enrichment. Database URLhttps://github.com/bel-enrichment/results

systems biology↗

bioRxiv2018

BioKEEN: A library for learning and evaluating biological knowledge graph embeddings

Knowledge graph embeddings (KGEs) have received significant attention in other domains due to their ability to predict links and create dense representations for graphs nodes and edges. However, the software ecosystem for their application to bioinformatics remains limited and inaccessible for users without expertise in programming and machine learning. Therefore, we developed BioKEEN (Biological KnowlEdge EmbeddiNgs) and PyKEEN (Python KnowlEdge EmbeddiNgs) to facilitate their easy use through an interactive command line interface. Finally, we present a case study in which we used a novel biological pathway mapping resource to predict links that represent pathway crosstalks and hierarchies.\n\nAvailabilityBioKEEN and PyKEEN are open source Python packages publicly available under the MIT License at https://github.com/SmartDataAnalytics/BioKEEN and https://github.com/SmartDataAnalytics/PyKEEN as well as through PyPI.

bioinformatics↗

bioRxiv2018

PathMe: Merging and exploring mechanistic pathway knowledge

BackgroundThe complexity of representing biological systems is compounded by an ever-expanding body of knowledge emerging from multi-omics experiments. A number of pathway databases have facilitated pathway-centric approaches that assist in the interpretation of molecular signatures yielded by these experiments. However, the lack of interoperability between pathway databases has hindered the ability to harmonize these resources and to exploit their consolidated knowledge. Such a unification of pathway knowledge is imperative in enhancing the comprehension and modeling of biological abstractions.\n\nResultsHere, we present PathMe, a Python package that transforms pathway knowledge from three major pathway databases into a unified abstraction using Biological Expression Language as the pivotal, integrative schema. PathMe is complemented by a novel web application (freely available at https://pathme.scai.fraunhofer.de/) which allows users to comprehensively explore pathway crosstalks and compare areas of consensus and discrepancies.\n\nConclusionsThis work has harmonized three major pathway databases and transformed them into a unified schema in order to gain a holistic picture of pathway knowledge. We demonstrate the utility of the PathMe framework in: i) integrating pathway landscapes at the database level, ii) comparing the degree of consensus at the pathway level, and iii) exploring pathway crosstalk and investigating consensus at the molecular level.

bioinformatics↗

bioRxiv2018

ComPath: An ecosystem for exploring, analyzing, and curating pathway databases

Although pathways are widely used for the analysis and representation of biological systems, their lack of clear boundaries, their dispersion across numerous databases, and the lack of interoperability impedes the evaluation of the coverage, agreements, and discrepancies between them. Here, we present ComPath, an ecosystem that supports curation of pathway mappings between databases and fosters the exploration of pathway knowledge through several novel visualizations. We have curated mappings between three of the major pathway databases and present a case study focusing on Parkinsons disease that illustrates how ComPath can generate new biological insights by identifying pathway modules, clusters, and cross-talks with these mappings. The ComPath source code and resources are available at https://github.com/ComPath and the web application can be accessed at http://compath.scai.fraunhofer.de/.

bioinformatics↗

bioRxiv2018

BEL Commons: an environment for exploration and analysis of networks encoded in Biological Expression Language

The rapid accumulation of knowledge in the field of systems and networks biology during recent years requires complex, but user-friendly and accessible web applications that allow from visualization to complex algorithmic analysis. While several web applications exist with various focuses on creation, revision, curation, storage, integration, collaboration, exploration, visualization, and analysis, many of these services remain disjoint and have yet to be packaged into a cohesive environment.\n\nHere, we present BEL Commons; an integrative knowledge discovery environment for networks encoded in the Biological Expression Language (BEL). Users can upload files in BEL to be parsed, validated, compiled, and stored with fine-granular permissions. After, users can summarize, explore, and optionally shared their networks with the scientific community. We have implemented a query builder wizard to help users find the relevant portions of increasingly large and complex networks and a visualization interface that allows them to explore their resulting networks. Finally, we have included a dedicated analytical service for performing data-driven analysis of knowledge networks to support hypothesis generation.\n\nThis web application can be freely accessed at https://bel-commons.scai.fraunhofer.de.

systems biology↗

bioRxiv2018

A systematic approach for identifying shared mechanisms in epilepsy and its comorbidities

Cross-sectional epidemiological studies have shown that the incidence of several nervous system diseases is more frequent in epilepsy patients than in the general population. Some comorbidities (e.g., Alzheimers disease and Parkinsons disease) are also risk factors for the development of seizures; suggesting they may share pathophysiological mechanisms with epilepsy.\n\nA literature-based approach was used to identify gene overlap between epilepsy and its comorbidities as a proxy for a shared genetic basis for disease, or genetic pleiotropy, as a first effort to identify shared mechanisms. While the results identified neurological disorders as the group of diseases with the highest gene overlap, this analysis was insufficient for identifying putative common mechanisms shared across epilepsy and its comorbidities. This motivated the use of a dedicated literature mining and knowledge assembly approach in which a cause-and-effect model of epilepsy was captured with Biological Expression Language.\n\nAfter enriching the knowledge assembly with information surrounding epilepsy, its risk factors, its comorbidities, and antiepileptic drugs, a novel comparative mechanism enrichment approach was used to propose several downstream effectors (including the GABA receptor, GABAergic pathways, etc.) that could explain the therapeutic effects carbamazepine in both the contexts of epilepsy and AD.\n\nWe have made the Epilepsy Knowledge Assembly available at https://www.scai.fraunhofer.de/content/dam/scai/de/downloads/bioinformatik/epilepsy.bel and queryable through NeuroMMSig at http://neurommsig.scai.fraunhofer.de. The source code used for analysis and tutorials for reproduction are available on GitHub at https://github.com/cthoyt/epicom.

systems biology↗