Obesity is a complex multifactorial disorder characterized by the excess accumulation of body fat that impairs human health due to the risk of developing other diseases, including cardiovascular and hepatic diseases, hypertension, diabetes, hyperlipidemia. Its spread has been progressively accelerating, resulting in an unprecedented epidemic with no significant signs of slowing down any time soon. Drug therapy via the proposal repurposing solutions can represent an actionable treatment strategy, even if the emergence of drug-induced adverse effects can affect the treatment of this pathology. In this study, we propose a network-based analysis to identify a list of drug candidates predicted to be repurposable for obesity that are unlikely to produce specific adverse side-effect, such as hepatic steatosis.

Dissecting the intricate regulatory dynamics between genes stands as a critical step towards the development of precise predictive models within biological systems. A highly effective strategy in this pursuit involves an examination of variations in correlation among gene pairs across different conditions trough differential gene correlation analysis. We anticipated that the application of this method to phylogenetically close plant species could reveal powerful insights on how genes’ relationships have a fundamental role in evolutionary dynamics. Building upon this principle, our investigation focused primarily on conducting a comprehensive differential correlation analysis of the roots’ orthologous genes of two closely related plant species: Cardamine hirsuta and Arabidopsis thaliana. By leveraging their shared phylogenetic proximity, we were able to draw comparisons that shed light on how evolutionary pressures might have shaped their gene regulatory networks. By integrating differential expression analysis, differential correlation analysis and functional enrichment analysis, we offer a robust framework for future studies aiming to unravel the complexities of adaptation and evolution across a wide range of biological systems.

In this article, we propose an updated version of our previously developed model for predicting drug-side effect associations, applied to two case studies: long QT syndrome and asthma. The classifier accepts the name of a specific drug side effect as input and outputs a list of drugs potentially associated with this side effect. By simulating how drug effects propagate within the interactome using the Random Walk with Restart algorithm, the classifier identifies genes potentially associated with the onset of the side effect. Based on the rationale that the more a drug perturbs these genes, the more likely it is to cause the side effect, the model identifies drugs potentially linked to the onset of the side effect. Moreover, the model enables the categorization of drugs into chemical subclasses using the ClassyFire schema, facilitating the analysis of complex side effects, such as asthma, through more specific mechanisms. The results show that the model identifies both drugs known to be associated with certain side effects, as well as drugs not officially reported by the FDA, demonstrating its generalizability and practical relevance. This method is also adaptable for analyzing other side effects.

Chronic obstructive pulmonary disease (COPD) is a lung disease causing hundred thousand of death each year worldwide and defined as a respiratory and airflow impairment majorly due to large and small airways dysfunctions. COPD could be considered as a syndrome that includes disease axes of variable pathological and clinical conditions. Despite recent advances, the comprehension of the molecular mechanisms responsible for COPD disease spectrum is far to be reached. Moreover, we should also consider continuous smoking exposure, which could lead to variability in the disease mechanisms and progression. Network-based multi-omics data integration can help to study the association between molecular determinants on diverse biomolecular layers in a disease context. In a previous study, we leveraged lung RNA-seq and DNA-methylation data of a COPD-control cohort to build a correlation-based integrated network (called coupled network), that helped to unveil genes involved in immune and inflammatory modulation of COPD. Therefore, in our previous study we highlighted the most important genes of the coupled network and inspected their single contribution to disease-related pathways. In this study we aim to overcome this limitation by performing a pathway activity analysis by considering the expression and DNA methylation profiles of coupled network genes. Moreover, we exploit this analysis to study the possible contribution of coupled network genes to the differential disease progression between current and former smokers patients.

Drug repurposing, also known as drug repositioning, is the process of identifying novel therapeutic indications for existing drugs, offering a cost-effective and time-efficient strategy to drug discovery. In this context, we developed a network-based algorithm, named SAveRUNNER (Searching off-lAbel dRUg aNd NEtwoRk), which predicts drug-disease associations by accounting for the interaction between the drug targets and disease-associated genes in the human interactome, implementing a novel network-based similarity measure that prioritizes associations between drugs and diseases locating in the same network neighborhoods. Following its successful applications to different disorders (such as viral infections and neurological diseases), in this study, we applied SAveRUNNER on a panel of 13 types of cancers using both disease-associated genes downloaded from widely-used databases and from gene expression data.

Despite the drug approval process consists of extremely rigorous clinical and preclinical studies, not all side effects are identified before its marketing, posing a significant risk to public health. Furthermore, considering the huge use of economic and human resources, in-silico predictive approaches for the identification of side effects are essential. In this study, we introduce a new method based on random walk with restart algorithm to delineate previously unidentified links between drugs and side effects, and we apply it on the drug-induced Asthma and long QT syndrome. We identified the genes potentially involved in the development of the analyzed side effect by comparing side-effect-related drugs with drugs not known to induce side effects. Analyzing the sets of genes most likely influenced by the perturbation of each individual drug, we observed that, on average, side-effect-related drugs perturb a higher percentage of genes involved in the development of side effects compared to side-effect-unrelated drugs. Based on this finding, we developed a classifier to explore all possible unknown associations between drugs and side effects. This method can be extended to the analysis of other side effects as well.

Neuroblastoma is a disease of disordered development accounting for 15% of childhood cancer deaths. The "cold" immunophenotype frequently occurring of these tumors is likely to contribute to its aggressiveness and refractoriness to treatments, including immune checkpoint blockade, observed in high risk neuroblastoma. The mechanisms that contribute to the cold immunostate have not been elucidated, yet. However, recent studies have reported the involvement of MYCN amplification in reducing the immune infiltrate in high-risk Neuroblastoma tumors. Its action mainly concerns suppressed interferon responses and pro-inflammatory pathways. An important pathway deputed to the activation of type I interferon responses and pro-inflammatory cytokines release is the cyclic GMP–AMP synthase (cGAS) – stimulator of interferon genes (STING) cytosolic DNA sensing pathway. Recent preclinical studies suggest a promising therapeutic effect of cGAS-STING pathway reactivation in Neuroblastomas. However, very little is known about the regulation of the cGAS-STING pathway in Neuroblastoma malignant cells, and its relationship with the MYCN amplification state. To this end, we performed a single-cell transcriptomic analysis of primary human Neuroblastoma cells compared with their normal fetal and embryonic progenitors. The results of the high-resolution analysis of cGAS-STING pathway showed that Neuroblastomas malignant cells have a much lower expression of this pathway compared to normal progenitors and other cell phenotypes populating the tumor microenvironment, possibly acquiring an evolutionary advantage. Moreover, the cGAS-STING pathway anticorrelated with MYCN expression suggesting a putative regulatory mechanism of the STING pathway.

microRNAs play an important role in post-transcriptional gene regulation. Recently, viral microRNAs have been discovered in several viruses, including Hepatitis B virus. This brief work explores bioinformatics tools for viral/host miRNA research and provides insights into the roles of miRNAs in HBV infection, offering an overview of this field, in order to facilitate the selection of the most suitable bioinformatics tools according to individual needs and research goals.

SUMMARY: We present SWIMmeR, an open-source version of its predecessor SWIM (SWitchMiner) that is a network-based tool for mining key (switch) genes that are associated with intriguing patterns of molecular co-abundance and may play a crucial role in phenotypic transitions in various biological settings. SWIM was originally written in MATLAB®, a proprietary programming language that requires the purchase of a license to install, manipulate, operate and run the software. Over the last years, SWIM has sparked a widespread interest within the scientific community thanks to the promising results obtained through its application in a broad range of phenotype-specific scenarios, spanning from complex diseases to grapevine berry maturation. This success has created the call for it to be distributed in a freely accessible, open-source, runtime environment, such as R, aimed at a general audience of non-expert users that cannot afford the leading proprietary solution. SWIMmeR is provided as a comprehensive collection of R functions and it also includes several additional features that make it less intensive in terms of computer time and more efficient in terms of usability and further implementation and extension. AVAILABILITY AND IMPLEMENTATION: The SWIMmeR source code is freely available at https://github.com/sportingCode/SWIMmeR.git, along with a practical user guide, including a usage example of its application on breast cancer dataset. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

BACKGROUND: Gene expression is the result of the balance between transcription and degradation. Recent experimental findings have shown fine and specific regulation of RNA degradation and the presence of various molecular machinery purposely devoted to this task, such as RNA binding proteins, non-coding RNAs, etc. A biological process can be studied by measuring time-courses of RNA abundance in response of internal and/or external stimuli, using recent technologies, such as the microarrays or the Next Generation Sequencing devices. Unfortunately, the picture provided by looking only at the transcriptome abundance may not gain insight into its dynamic regulation. By contrast, independent simultaneous measurement of RNA expression and half-lives could provide such valuable additional insight. A computational approach to the estimation of RNAs half-lives from RNA expression time profiles data, can be a low-cost alternative to its experimental measurement which may be also affected by various artifacts. RESULTS: Here we present a computational methodology, called StaRTrEK (STAbility Rates ThRough Expression Kinetics), able to estimate half-life values basing only on genome-wide gene expression time series without transcriptional inhibition. The StaRTrEK algorithm makes use of a simple first order kinetic model and of a [Formula: see text]-norm regularized least square optimization approach to find its parameter values. Estimates provided by StaRTrEK are validated using simulated data and three independent experimental datasets of two short (6 samples) and one long (48 samples) time-courses. CONCLUSIONS: We believe that our algorithm can be used as a fast valuable computational complement to time-course experimental gene expression studies by adding a relevant kinetic property, i.e. the RNA half-life, with a strong biological interpretation, thus providing a dynamic picture of what is going in a cell during the biological process under study.

BACKGROUND: Recently, we developed a mathematical model for identifying putative competing endogenous RNA (ceRNA) interactions. This methodology has aroused a broad acknowledgment within the scientific community thanks to the encouraging results achieved when applied to breast invasive carcinoma, leading to the identification of PVT1, a long non-coding RNA functioning as ceRNA for the miR-200 family. The main shortcoming of the model is that it is no freely available and implemented in MATLAB®, a proprietary programming platform requiring a paid license for installing, operating, manipulating, and running the software. RESULTS: Breaking through these model limitations demands to distribute it in an open-source, freely accessible environment, such as R, designed for an ordinary audience of users that are not able to afford a proprietary solution. Here, we present SPINNAKER (SPongeINteractionNetworkmAKER), the open-source version of our widely established mathematical model for predicting ceRNAs crosstalk, that is released as an exhaustive collection of R functions. SPINNAKER has been even designed for providing many additional features that facilitate its usability, make it more efficient in terms of further implementation and extension, and less intense in terms of computational execution time. CONCLUSIONS: SPINNAKER source code is freely available at https://github.com/sportingCode/SPINNAKER.git together with a thoroughgoing PPT-based guideline. In order to help users get the key points more conveniently, also a practical R-styled plain-text guideline is provided. Finally, a short movie is available to help the user to set the own directory, properly.

BACKGROUND: Currently, no proven effective drugs for the novel coronavirus disease COVID-19 exist and despite widespread vaccination campaigns, we are far short from herd immunity. The number of people who are still vulnerable to the virus is too high to hamper new outbreaks, leading a compelling need to find new therapeutic options devoted to combat SARS-CoV-2 infection. Drug repurposing represents an effective drug discovery strategy from existing drugs that could shorten the time and reduce the cost compared to de novo drug discovery. RESULTS: We developed a network-based tool for drug repurposing provided as a freely available R-code, called SAveRUNNER (Searching off-lAbel dRUg aNd NEtwoRk), with the aim to offer a promising framework to efficiently detect putative novel indications for currently marketed drugs against diseases of interest. SAveRUNNER predicts drug-disease associations by quantifying the interplay between the drug targets and the disease-associated proteins in the human interactome through the computation of a novel network-based similarity measure, which prioritizes associations between drugs and diseases located in the same network neighborhoods. CONCLUSIONS: The algorithm was successfully applied to predict off-label drugs to be repositioned against the new human coronavirus (2019-nCoV/SARS-CoV-2), and it achieved a high accuracy in the identification of well-known drug indications, thus revealing itself as a powerful tool to rapidly detect potential novel medical indications for various drugs that are worth of further investigation. SAveRUNNER source code is freely available at https://github.com/giuliafiscon/SAveRUNNER.git , along with a comprehensive user guide.

The novelty of new human coronavirus COVID-19/SARS-CoV-2 and the lack of effective drugs and vaccines gave rise to a wide variety of strategies employed to fight this worldwide pandemic. Many of these strategies rely on the repositioning of existing drugs that could shorten the time and reduce the cost compared to de novo drug discovery. In this study, we presented a new network-based algorithm for drug repositioning, called SAveRUNNER (Searching off-lAbel dRUg aNd NEtwoRk), which predicts drug-disease associations by quantifying the interplay between the drug targets and the disease-specific proteins in the human interactome via a novel network-based similarity measure that prioritizes associations between drugs and diseases locating in the same network neighborhoods. Specifically, we applied SAveRUNNER on a panel of 14 selected diseases with a consolidated knowledge about their disease-causing genes and that have been found to be related to COVID-19 for genetic similarity (i.e., SARS), comorbidity (e.g., cardiovascular diseases), or for their association to drugs tentatively repurposed to treat COVID-19 (e.g., malaria, HIV, rheumatoid arthritis). Focusing specifically on SARS subnetwork, we identified 282 repurposable drugs, including some the most rumored off-label drugs for COVID-19 treatments (e.g., chloroquine, hydroxychloroquine, tocilizumab, heparin), as well as a new combination therapy of 5 drugs (hydroxychloroquine, chloroquine, lopinavir, ritonavir, remdesivir), actually used in clinical practice. Furthermore, to maximize the efficiency of putative downstream validation experiments, we prioritized 24 potential anti-SARS-CoV repurposable drugs based on their network-based similarity values. These top-ranked drugs include ACE-inhibitors, monoclonal antibodies (e.g., anti-IFNγ, anti-TNFα, anti-IL12, anti-IL1β, anti-IL6), and thrombin inhibitors. Finally, our findings were in-silico validated by performing a gene set enrichment analysis, which confirmed that most of the network-predicted repurposable drugs may have a potential treatment effect against human coronavirus infections.

BACKGROUND: miRNAs regulate the expression of several genes with one miRNA able to target multiple genes and with one gene able to be simultaneously targeted by more than one miRNA. Therefore, it has become indispensable to shorten the long list of miRNA-target interactions to put in the spotlight in order to gain insight into understanding the regulatory mechanism orchestrated by miRNAs in various cellular processes. A reasonable solution is certainly to prioritize miRNA-target interactions to maximize the effectiveness of the downstream analysis. RESULTS: We propose a new and easy-to-use web tool MIENTURNET (MicroRNA ENrichment TURned NETwork) that receives in input a list of miRNAs or mRNAs and tackles the problem of prioritizing miRNA-target interactions by performing a statistical analysis followed by a fully featured network-based visualization and analysis. The statistics is used to assess the significance of an over-representation of miRNA-target interactions and then MIENTURNET filters based on the statistical significance associated with each miRNA-target interaction. In addition, the holistic approach of the network theory is used to infer possible evidences of miRNA regulation by capturing emergent properties of the miRNA-target regulatory network that would be not evident through a pairwise analysis of the individual components. CONCLUSION: MIENTURNET offers the possibility to consistently perform both statistical and network-based analyses by using only a single tool leading to a more effective prioritization of the miRNA-target interactions. This has the potential to avoid researchers without computational and informatics skills to navigate multiple websites and thus to independently investigate miRNA activity in every cellular process of interest in an easy and at the same time exhaustive way thanks to the intuitive web interface. The web application along with a well-documented and comprehensive user guide are freely available at http://userver.bio.uniroma1.it/apps/mienturnet/ without any login requirement.

The transcriptome in a cell is finely regulated by a large number of molecular mechanisms able to control the balance between mRNA production and degradation. Recent experimental findings have evidenced that fine and specific regulation of degradation is needed for proper orchestration of a global cell response to environmental conditions. We developed a computational technique based on stochastic modeling, to infer condition-specific individual mRNA half-lives directly from gene expression time-courses. Predictions from our method were validated by experimentally measured mRNA decay rates during the intraerythrocytic developmental cycle of Plasmodium falciparum. We then applied our methodology to publicly available data on the reproductive and metabolic cycle of budding yeast. Strikingly, our analysis revealed, in all cases, the presence of periodic changes in decay rates of sequentially induced genes and co-ordination strategies between transcription and degradation, thus suggesting a general principle for the proper coordination of transcription and degradation machinery in response to internal and/or external stimuli.

Vaccine research is a combinatorial science requiring computational analysis of vaccine components, formulations and optimization. We have developed a framework that combines computational tools for the study of immune function and vaccine development. This framework, named ImmunoGrid combines conceptual models of the immune system, models of antigen processing and presentation, system-level models of the immune system, Grid computing, and database technology to facilitate discovery, formulation and optimization of vaccines. ImmunoGrid modules share common conceptual models and ontologies. The ImmunoGrid portal offers access to educational simulators where previously defined cases can be displayed, and to research simulators that allow the development of new, or tuning of existing, computational models. The portal is accessible at .

BACKGROUND: The efficiency of lymph nodes depends on tissue structure and organization, which allow the coordination of lymphocyte traffic. Despite their essential role, our understanding of lymph node specific mechanisms is still incomplete and currently a topic of intense research. RESULTS: In this paper, we present a hybrid discrete/continuous model of the lymph node, accounting for differences in cell velocity and chemotactic response, influenced by the spatial compartmentalization of the lymph node and the regulation of cells migration, encounter, and antigen presentation during the inflammation process. CONCLUSION: Our model reproduces the correct timing of an immune response, including the observed time delay between duplication of T helper cells and duplication of B cells in response to antigen exposure. Furthermore, we investigate the consequences of the absence of dendritic cells at different times during infection, and the dependence of system dynamics on the regulation of lymphocyte exit from lymph nodes. In both cases, the model predicts the emergence of an impaired immune response, i.e., the response is significantly reduced in magnitude. Dendritic cell removal is also shown to delay the response time with respect to normal conditions.