Sources Of Biological Information Research Articles

Motif-Aware miRNA-Disease Association Prediction via Hierarchical Attention Network.

As post-transcriptional regulators of gene expression, micro-ribonucleic acids (miRNAs) are regarded as potential biomarkers for a variety of diseases. Hence, the prediction of miRNA-disease associations (MDAs) is of great significance for an in-depth understanding of disease pathogenesis and progression. Existing prediction models are mainly concentrated on incorporating different sources of biological information to perform the MDA prediction task while failing to consider the fully potential utility of MDA network information at the motif-level. To overcome this problem, we propose a novel motif-aware MDA prediction model, namely MotifMDA, by fusing a variety of high- and low-order structural information. In particular, we first design several motifs of interest considering their ability to characterize how miRNAs are associated with diseases through different network structural patterns. Then, MotifMDA adopts a two-layer hierarchical attention to identify novel MDAs. Specifically, the first attention layer learns high-order motif preferences based on their occurrences in the given MDA network, while the second one learns the final embeddings of miRNAs and diseases through coupling high- and low-order preferences. Experimental results on two benchmark datasets have demonstrated the superior performance of MotifMDA over several state-of-the-art prediction models. This strongly indicates that accurate MDA prediction can be achieved by relying solely on MDA network information. Furthermore, our case studies indicate that the incorporation of motif-level structure information allows MotifMDA to discover novel MDAs from different perspectives.

Организация и методика проведения полевой практики по ботанике в вузе в условиях дистанционного обучения

The trends in the formation of a digital society serve as benchmarks for the current and prospective development of higher pedagogical education. Therefore, one of the goals of biological and ecological education for future teachers is to master modern digital technologies. Federal projects for creating a digital educational environment include the development of digital services and content for educational activities. Thus, the development of distance learning technologies and blended learning has become a crucial condition for the digital transformation of biology and ecology teaching in higher education. The Federal State Educational Standards for Higher Education (FGOS VO) require the learning outcomes to reflect the components of information culture for future biology teachers and bioecologists. This includes skills such as obtaining necessary information from dictionaries, atlases, guides, the ability to navigate various sources of biological information, critically evaluate and interpret information about living and non-living nature in the media and other sources, and the ability to use information and communication technologies in solving practical tasks. In this regard, organizing field practice for biology students in botany under distance learning conditions is an important component in the subject, meta-subject, and methodological preparation of future biology teachers and bioecology specialists. The accessibility of modern information resources to students, including those with limited capabilities and athletes, in any location and time using distance technologies emphasizes the need to improve their information culture. By engaging students remotely in the study of living nature through mobile devices, virtual and augmented reality, university teachers shape their knowledge and skills in botany, ICT competencies, and information culture, which is part of general human culture and an important element in the development of every individual. Objective: To improve the effectiveness of organizing and conducting field practice for bioecology students in botany under conditions of distance and blended learning. Method or Methodology: The publication is based on information, technological, and competency-based pedagogical approaches. The article utilizes group natural science and pedagogical observations, mathematical methods, and the analysis of students’ activities resulting from individual independent collection of plant material with subsequent analysis and chamber processing. Results: Positive results have been obtained, allowing for the recommendation of implementing distance, mobile, and immersive technologies for organizing and conducting field practices in biology. Application Area of Results: The presented results can be applied in conducting educational activities in universities under conditions of blended and inclusive learning, particularly in biology field practices, both online and offline.

Trypsin Encapsulation in the Zeolitic Imidazolate Framework for Low-Molecular Weight Protein Analysis with High Selectivity and Efficiency.

Low-molecular weight proteins (LWPs) are important sources of biological information in biomarkers, signaling molecules, and pathology. However, the separation and analysis of LWPs in complex biological samples are challenging, mainly due to their low abundance and the complex sample pretreatment procedure. Herein, trypsin modified by poly(acrylic acid) (PAA) was encapsulated by a zeolitic imidazolate framework (ZIF-L). Mesopores were formed on the ZIF-L with the introduction of PAA. An alternative strategy for separation and pretreatment of LWPs was developed based on the prepared ZIF-L-encapsulated trypsin with adjustable pore size. The mesoporous structure of the prepared materials selectively excluded high-molecular weight proteins from the reaction system, allowing LWPs to enter the pores and react with the internal trypsin, resulting in an improved separation efficiency. The hydrophobicity of the ZIF-L simplified the digestion process by inducing significant structural changes in substrate proteins. In addition, the enzymatic activity was significantly enhanced by the developed encapsulation method that maintained the enzyme conformation, allowed low mass transfer resistance, and possessed a high enzyme-to-substrate ratio. As a result, the ZIF-L-encapsulated trypsin can achieve highly selective separation, valid denaturation, and efficient digestion of LWPs in a short time by simply mixing with substrate proteins, greatly simplifying the separation and pretreatment process of the traditional hydrolysis method. The prepared materials and the developed strategy demonstrated an excellent size-selective assay performance in model protein mixtures, showing great potential in the application of proteomics analysis.

Representation Learning of Biological Concepts: A Systematic Review

Objective: Representation learning in the context of biological concepts involves acquiring their numerical representations through various sources of biological information, such as sequences, interactions, and literature. This study has conducted a comprehensive systematic review by analyzing both quantitative and qualitative data to provide an overview of this field. Methods: Our systematic review involved searching for articles on the representation learning of biological concepts in PubMed and EMBASE databases. Among the 507 articles published between 2015 and 2022, we carefully screened and selected 65 papers for inclusion. We then developed a structured workflow that involved identifying relevant biological concepts and data types, reviewing various representation learning techniques, and evaluating downstream applications for assessing the quality of the learned representations. Results: The primary focus of this review was on the development of numerical representations for gene/DNA/RNA entities. We have found Word2Vec to be the most commonly used method for biological representation learning. Moreover, several studies are increasingly utilizing state-of-the-art large language models to learn numerical representations of biological concepts. We also observed that representations learned from specific sources were typically used for single downstream applications that were relevant to the source. Conclusion: Existing methods for biological representation learning are primarily focused on learning representations from a single data type, with the output being fed into predictive models for downstream applications. Although there have been some studies that have explored the use of multiple data types to improve the performance of learned representations, such research is still relatively scarce. In this systematic review, we have provided a summary of the data types, models, and downstream applications used in this task.

Precision prognosis of colorectal cancer: a multi-tiered model integrating microsatellite instability genes and clinical parameters.

Prognostic assessment for colorectal cancer (CRC) displays substantial heterogeneity, as reliance solely on traditional TNM staging falls short of achieving precise individualized predictions. The integration of diverse biological information sources holds the potential to enhance prognostic accuracy. To establish a comprehensive multi-tiered precision prognostic evaluation system for CRC by amalgamating gene expression profiles, clinical characteristics, and tumor microsatellite instability (MSI) status in CRC patients. We integrated genomic data, clinical information, and survival follow-up data from 483 CRC patients obtained from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. MSI-related gene modules were identified using differential expression analysis and Weighted Gene Co-expression Network Analysis (WGCNA). Three prognostic models were constructed: MSI-Related Gene Prognostic Model (Model I), Clinical Prognostic Model (Model II), and Integrated Multi-Layered Prognostic Model (Model III) by combining clinical features. Model performance was assessed and compared using Receiver Operating Characteristic (ROC) curves, Kaplan-Meier analysis, and other methods. Six MSI-related genes were selected for constructing Model I (AUC = 0.724); Model II used two clinical features (AUC = 0.684). Compared to individual models, the integrated Model III exhibited superior performance (AUC = 0.825) and demonstrated good stability in an independent dataset (AUC = 0.767). This study successfully developed and validated a comprehensive multi-tiered precision prognostic assessment model for CRC, providing an effective tool for personalized medical management of CRC.

Bioinformatic prediction of the molecular links between Alzheimer's disease and diabetes mellitus.

Alzheimer's disease (AD) and type 2 diabetes mellitus (DM2) are chronic degenerative diseases with complex molecular processes that are potentially interconnected. The aim of this work was to predict the potential molecular links between AD and DM2 from different sources of biological information. In this work, data mining of nine databases (DisGeNET, Ensembl, OMIM, Protein Data Bank, The Human Protein Atlas, UniProt, Gene Expression Omnibus, Human Cell Atlas, and PubMed) was performed to identify gene and protein information that was shared in AD and DM2. Next, the information was mapped to human protein-protein interaction (PPI) networks based on experimental data using the STRING web platform. Then, gene ontology biological process (GOBP) and pathway analyses with EnrichR showed its specific and shared biological process and pathway deregulations. Finally, potential biomarkers and drug targets were predicted with the Metascape platform. A total of 1,551 genes shared in AD and DM2 were identified. The highest average degree of nodes within the PPI was for DM2 (average = 2.97), followed by AD (average degree = 2.35). GOBP for AD was related to specific transcriptional and translation genetic terms occurring in neurons cells. The GOBP and pathway information for the association AD-DM2 were linked mainly to bioenergetics and cytokine signaling. Within the AD-DM2 association, 10 hub proteins were identified, seven of which were predicted to be present in plasma and exhibit pharmacological interaction with monoclonal antibodies in use, anticancer drugs, and flavonoid derivatives. Our data mining and analysis strategy showed that there are a plenty of biological information based on experiments that links AD and DM2, which could provide a rational guide to design further diagnosis and treatment for AD and DM2.

Hybrid Classification Model for Biomedical Data Analysis

The paper describes a method for constructing a hybrid classification model that allows combining several sources of biological information in order to build a classifier to identify subtypes of complex diseases. The distinctive feature of the method is its adaptive nature, i.e. the ability to build efficient classifiers regardless of data types, as well as a multi-criteria approach to evaluate the effectiveness of a classification. The testing results on real biomedical data showed the advantages of the proposed hybrid model in comparison with individual classifiers.

Biological Random Walks: multi-omics integration for disease gene prioritization.

Over the past decade, network-based approaches have proven useful in identifying disease modules within the human interactome, often providing insights into key mechanisms and guiding the quest for therapeutic targets. This is all the more important, since experimental investigation of potential gene candidates is an expensive task, thus not always a feasible option. On the other hand, many sources of biological information exist beyond the interactome and an important research direction is the design of effective techniques for their integration. In this work, we introduce the Biological Random Walks (BRW) approach for disease gene prioritization in the human interactome. The proposed framework leverages multiple biological sources within an integrated framework. We perform an extensive, comparative study of BRW's performance against well-established baselines. All codes are publicly available and can be downloaded at https://github.com/LeoM93/BiologicalRandomWalks. We used publicly available datasets, details on their retrieval and preprocessing are provided in the Supplementary Material. Supplementary data are available at Bioinformatics online.

Efficient mass spectrometric characterization and classification of methylmalonic aciduria subtypes through urinary and blood metabolic profiles fusion

Efficient subtype classification utilizing multiple biological information sources is clinically practical for precision treatment of inborn errors of metabolism (IEMs). This study utilized urinary GC–MS and dried blood spot MS/MS to enable complementary mass spectrometric characterization of pathological information for methylmalonic aciduria (MMA) subtypes. A novel mid-level data fusion strategy was subsequently described to effectively detect their subtle metabolic perturbations. In the proposed strategy, multivariate advantage was extracted via considering variable relationships in individual data blocks, separately. Further, it was extended to exploiting partial correlation across multiple data blocks, which induced the models between one data block and the first principal component (PC1) of another one for more valuable information recovery. The continuous values of PC1 replaced the traditional binary class labels, enabling suitable representation of disease heterogeneity numerically and subsequent accurate disease detection. Based on the unique role in exploratory data analysis, partial least squares discriminant analysis (PLS-DA) was coupled with bootstrap to form ensemble feature selection framework. It allowed the novel mid-level data fusion strategy to screen stable significant features. Investigated by two common MMA subtypes (mut and cblC) using urinary and blood metabolic profiles, the results showed that the novel mid-level data fusion strategy outperformed the traditional data fusion approaches both in predictive accuracy and biological interpretation. Besides, correlation network of the identified stable informative metabolites was visualized by chord plots, revealing different between-block biological interaction pattern for mut and cblC. Especially, in mut subtype, strong interactions could be occurred between the urinary metabolite of 3-OH-propionic-2 and two blood metabolite ratios (C3/C2 and C3/C0), separately. The findings deepened the biological insights into the disease pathology of mut and cblC. The integration of multiple analytical sources combined with the proposed novel mid-level data fusion strategy thus opened the possibilities to achieve desirable subtype classification for MMA. It suitably guided the early and timely medical intervention for IEMs.

A deep learning method for repurposing antiviral drugs against new viruses via multi-view nonnegative matrix factorization and its application to SARS-CoV-2.

The outbreak of COVID-19 caused by SARS-coronavirus (CoV)-2 has made millions of deaths since 2019. Although a variety of computational methods have been proposed to repurpose drugs for treating SARS-CoV-2 infections, it is still a challenging task for new viruses, as there are no verified virus-drug associations (VDAs) between them and existing drugs. To efficiently solve the cold-start problem posed by new viruses, a novel constrained multi-view nonnegative matrix factorization (CMNMF) model is designed by jointly utilizing multiple sources of biological information. With the CMNMF model, the similarities of drugs and viruses can be preserved from their own perspectives when they are projected onto a unified latent feature space. Based on the CMNMF model, we propose a deep learning method, namely VDA-DLCMNMF, for repurposing drugs against new viruses. VDA-DLCMNMF first initializes the node representations of drugs and viruses with their corresponding latent feature vectors to avoid a random initialization and then applies graph convolutional network to optimize their representations. Given an arbitrary drug, its probability of being associated with a new virus is computed according to their representations. To evaluate the performance of VDA-DLCMNMF, we have conducted a series of experiments on three VDA datasets created for SARS-CoV-2. Experimental results demonstrate that the promising prediction accuracy of VDA-DLCMNMF. Moreover, incorporating the CMNMF model into deep learning gains new insight into the drug repurposing for SARS-CoV-2, as the results of molecular docking experiments reveal that four antiviral drugs identified by VDA-DLCMNMF have the potential ability to treat SARS-CoV-2 infections.

Gene prediction of aging-related diseases based on DNN and Mashup

BackgroundAt present, the bioinformatics research on the relationship between aging-related diseases and genes is mainly through the establishment of a machine learning multi-label model to classify each gene. Most of the existing methods for predicting pathogenic genes mainly rely on specific types of gene features, or directly encode multiple features with different dimensions, use the same encoder to concatenate and predict the final results, which will be subject to many limitations in the applicability of the algorithm. Possible shortcomings of the above include: incomplete coverage of gene features by a single type of biomics data, overfitting of small dimensional datasets by a single encoder, or underfitting of larger dimensional datasets.MethodsWe use the known gene disease association data and gene descriptors, such as gene ontology terms (GO), protein interaction data (PPI), PathDIP, Kyoto Encyclopedia of genes and genomes Genes (KEGG), etc, as input for deep learning to predict the association between genes and diseases. Our innovation is to use Mashup algorithm to reduce the dimensionality of PPI, GO and other large biological networks, and add new pathway data in KEGG database, and then combine a variety of biological information sources through modular Deep Neural Network (DNN) to predict the genes related to aging diseases.Result and conclusionThe results show that our algorithm is more effective than the standard neural network algorithm (the Area Under the ROC curve from 0.8795 to 0.9153), gradient enhanced tree classifier and logistic regression classifier. In this paper, we firstly use DNN to learn the similar genes associated with the known diseases from the complex multi-dimensional feature space, and then provide the evidence that the assumed genes are associated with a certain disease.

How Molecules Became Signs

To explore how molecules became signs I will ask: “What sort of process is necessary and sufficient to treat a molecule as a sign?” This requires focusing on the interpreting system and its interpretive competence. To avoid assuming any properties that need to be explained I develop what I consider to be a simplest possible molecular model system which only assumes known physics and chemistry but nevertheless exemplifies the interpretive properties of interest. Three progressively more complex variants of this model of interpretive competence are developed that roughly parallel an icon-index-symbol hierarchic scaffolding logic. The implication of this analysis is a reversal of the current dogma of molecular and evolutionary biology which treats molecules like DNA and RNA as the original sources of biological information. Instead I argue that the structural characteristics of these molecules have provided semiotic affordances that the interpretive dynamics of viruses and cells have taken advantage of. These molecules are not the source of biological information but are instead semiotic artifacts onto which dynamical functional constraints have been progressively offloaded during the course of evolution.

Spatial Information in the Emergence of Life.

Information in living systems is part of a complex relationship between the internal organization and functionality of life. In a cell, both genetic-coding sequences and molecular-shape recognition are sources of biological information. For folded polymers, its spatial arrangement contains general references about conditions that shaped them, as imprints, defining the data for spatial (conformational) information. Considering the origin of life problem, prebiotic dynamics of matching and transfer of molecular shapes may emerge as a flow of information in prebiotic assemblages. The property of carrying information in molecular conformations is only displayed at this system organization level. Accordingly, spatial information is a resource for active system responses toward milieu disturbances. Propagation of resilient conformations could be the substrate for structural maintenance through dynamical molecular scaffolding. The above is a basis for adaptive behavior in potentially biogenic systems. Starting from non-structured populations of carrying-information polymers, in the present contribution, we advance toward an entire theoretical framework considering the active role of these polymers to support the emergence of adaptive response in systems that manage conformational information flow. We discuss this scenario as a previous step for the arising of sequential information carried out by genetic polymers.

Identifying potential association on gene-disease network via dual hypergraph regularized least squares

BackgroundIdentifying potential associations between genes and diseases via biomedical experiments must be the time-consuming and expensive research works. The computational technologies based on machine learning models have been widely utilized to explore genetic information related to complex diseases. Importantly, the gene-disease association detection can be defined as the link prediction problem in bipartite network. However, many existing methods do not utilize multiple sources of biological information; Additionally, they do not extract higher-order relationships among genes and diseases.ResultsIn this study, we propose a novel method called Dual Hypergraph Regularized Least Squares (DHRLS) with Centered Kernel Alignment-based Multiple Kernel Learning (CKA-MKL), in order to detect all potential gene-disease associations. First, we construct multiple kernels based on various biological data sources in gene and disease spaces respectively. After that, we use CAK-MKL to obtain the optimal kernels in the two spaces respectively. To specific, hypergraph can be employed to establish higher-order relationships. Finally, our DHRLS model is solved by the Alternating Least squares algorithm (ALSA), for predicting gene-disease associations.ConclusionComparing with many outstanding prediction tools, DHRLS achieves best performance on gene-disease associations network under two types of cross validation. To verify robustness, our proposed approach has excellent prediction performance on six real-world networks. Our research work can effectively discover potential disease-associated genes and provide guidance for the follow-up verification methods of complex diseases.

A Machine Learning-Based Biological Drug-Target Interaction Prediction Method for a Tripartite Heterogeneous Network.

Drug repositioning is the identification of interactions between drugs and target proteins in pharmaceutical sciences. Traditional large-scale validation through chemical experiments is time-consuming and expensive, while drug repositioning can drastically decrease the cost and duration taken by traditional drug development. With the rapid advancement of high-throughput technologies and the explosion of various biological and medical data, computational drug repositioning methods have been used to systematically identify potential drug–target interactions. Some of them are based on a particular class of machine learning algorithms called kernel methods. In this paper, we propose a new machine learning prediction method combining multiple kernels into a tripartite heterogeneous drug–target–disease interaction spaces in order to integrate multiple sources of biological information simultaneously. This novel network algorithm extends the traditional drug–target interaction bipartite graph to the third disease layer. Meanwhile, Gaussian kernel functions on heterogeneous networks and the regularized least square method of the Kronecker product are used to predict new drug–target interactions. The values of AUPR (area under the precision–recall curve) and AUC (the area under the receiver operating characteristic curve) of the proposed algorithm are significantly improved. Especially, the AUC values are improved to 0.99, 0.99, 0.97, and 0.96 on four benchmark data sets. These experimental results substantiate that the network topology can be used for predicting drug–target interactions.

GALLO: An R package for genomic annotation and integration of multiple data sources in livestock for positional candidate loci.

BackgroundThe development of high-throughput sequencing and genotyping methodologies has enabled the identification of thousands of genomic regions associated with several complex traits. The integration of multiple sources of biological information is a crucial step required to better understand patterns regulating the development of these traits.FindingsGenomic Annotation in Livestock for positional candidate LOci (GALLO) is an R package developed for the accurate annotation of genes and quantitative trait loci (QTLs) located in regions identified in common genomic analyses performed in livestock, such as genome-wide association studies and transcriptomics using RNA sequencing. Moreover, GALLO allows the graphical visualization of gene and QTL annotation results, data comparison among different grouping factors (e.g., methods, breeds, tissues, statistical models, studies), and QTL enrichment in different livestock species such as cattle, pigs, sheep, and chickens.ConclusionsConsequently, GALLO is a useful package for annotation, identification of hidden patterns across datasets, and data mining previously reported associations, as well as the efficient examination of the genetic architecture of complex traits in livestock.

Estimation of Energy Absorption Capability of Arm Using Force Myography for Stable Human-Machine Interaction.

Human-robot interactions help in various industries and enhance the user experience in different ways. However, constant safety monitoring is needed in environments where human users are at risk, such as rehabilitation therapy, space exploration, or mining. One way to improve safety and performance in robotic tasks is to include biological information of the user in the control system. This can help regulate the energy that is delivered to the user. In this work, we estimate the energy absorbing capabilities of the human arm, using the metric Excess of Passivity (EOP). EOP data from healthy subjects were obtained based on Forcemyography of the subjects' arm, to expand the sources of biological information and improve estimations.Clinical relevance- This protocol can help determine the ability of rehabilitation patients to withstand robotic stimulation with high amplitudes of therapeutic forces, as needed in assistive therapy.

A novel approach to triple-negative breast cancer molecular classification reveals a luminal immune-positive subgroup with good prognoses

Triple-negative breast cancer is a heterogeneous disease characterized by a lack of hormonal receptors and HER2 overexpression. It is the only breast cancer subgroup that does not benefit from targeted therapies, and its prognosis is poor. Several studies have developed specific molecular classifications for triple-negative breast cancer. However, these molecular subtypes have had little impact in the clinical setting. Gene expression data and clinical information from 494 triple-negative breast tumors were obtained from public databases. First, a probabilistic graphical model approach to associate gene expression profiles was performed. Then, sparse k-means was used to establish a new molecular classification. Results were then verified in a second database including 153 triple-negative breast tumors treated with neoadjuvant chemotherapy. Clinical and gene expression data from 494 triple-negative breast tumors were analyzed. Tumors in the dataset were divided into four subgroups (luminal-androgen receptor expressing, basal, claudin-low and claudin-high), using the cancer stem cell hypothesis as reference. These four subgroups were defined and characterized through hierarchical clustering and probabilistic graphical models and compared with previously defined classifications. In addition, two subgroups related to immune activity were defined. This immune activity showed prognostic value in the whole cohort and in the luminal subgroup. The claudin-high subgroup showed poor response to neoadjuvant chemotherapy. Through a novel analytical approach we proved that there are at least two independent sources of biological information: cellular and immune. Thus, we developed two different and overlapping triple-negative breast cancer classifications and showed that the luminal immune-positive subgroup had better prognoses than the luminal immune-negative. Finally, this work paves the way for using the defined classifications as predictive features in the neoadjuvant scenario.

A Drug-Target Network-Based Supervised Machine Learning Repurposing Method Allowing the Use of Multiple Heterogeneous Information Sources.

Drug-target networks have an important role in pharmaceutical innovation, drug lead discovery, and recent drug repositioning tasks. Many different in silico approaches for the identification of new drug-target interactions have been proposed, many of them based on a particular class of machine learning algorithms called kernel methods. These pattern classification algorithms are able to incorporate previous knowledge in the form of similarity functions, i.e., a kernel, and they have been successful in a wide range of supervised learning problems. The selection of the right kernel function and its respective parameters can have a large influence on the performance of the classifier. Recently, multiple kernel learning algorithms have been introduced to address this problem, enabling one to combine multiple kernels into large drug-target interaction spaces in order to integrate multiple sources of biological information simultaneously. The Kronecker regularized least squares with multiple kernel learning (KronRLS-MKL) is a machine learning algorithm that aims at integrating heterogeneous information sources into a single chemogenomic space to predict new drug-target interactions. This chapter describes how to obtain data from heterogeneous sources and how to implement and use KronRLS-MKL to predict new interactions.

Integrative workflows for network analysis.

Due to genetic heterogeneity across patients, the identification of effective disease signatures and therapeutic targets is challenging. Addressing this challenge, we have previously developed a network-based approach, which integrates heterogeneous sources of biological information to identify disease specific core-regulatory networks. In particular, our workflow uses a multi-objective optimization function to calculate a ranking score for network components (e.g. feedback/feedforward loops) based on network properties, biomedical and high-throughput expression data. High ranked network components are merged to identify the core-regulatory network(s) that is then subjected to dynamical analysis using stimulus-response and in silico perturbation experiments for the identification of disease gene signatures and therapeutic targets. In a case study, we implemented our workflow to identify bladder and breast cancer specific core-regulatory networks underlying epithelial-mesenchymal transition from the E2F1 molecular interaction map.In this study, we review our workflow and described how it has developed over time to understand the mechanisms underlying disease progression and prediction of signatures for clinical decision making.