Mechanotransduction is the process that enables the conversion of mechanical cues into biochemical signaling. While all our cells are well known to be sensitive to such stimuli, the details of the systemic interaction between mechanical input and inflammation are not well integrated. Often, indeed, they are considered and studied in relatively compartmentalized areas, and we therefore argue here that to understand the relationship of mechanical stimuli with inflammation – with a high translational potential - it is crucial to offer and analyze a unified view of mechanotransduction. We therefore present here pathway representation, recollected with the standard systems biology markup language (SBML) and explored with network biology approaches, offering RAC1 as an exemplar and emerging molecule with potential for medical translation.

Personalized medicine strategies are gaining momentum nowadays, enabling the introduction of targeted treatments based on individual differences that can lead to greater therapeutic efficacy by reducing adverse effects. Despite its crucial role, studying the contribution of the immune system (IS) in this context is difficult because of the intricate interplay between host, pathogen, therapy, and other external stimuli. To address this problem, a multidisciplinary approach involving in silico models can be of great help. In this perspective, we will discuss the use of a well-established agent-based model of the immune response, C-ImmSim, to study the relationship between long-lasting diseases and the combined effects of IS, drug therapies and exogenous factors such as physical activity and dietary habits.

Leishmania spp. commonly infects phagocytic cells of the immune system, particularly macrophages, employing various immune evasion strategies that enable their survival by altering the intracellular environment. In mammals, these parasites establish persistent infections by modulating gene expression in macrophages, thus interfering with immune signaling and response pathways, ultimately creating a favorable environment for the parasite’s survival and reproduction. In this study, our objective was to use data mining and subsequent filtering techniques to identify the genes that play a crucial role in the infection process of Leishmania spp. We aimed to pinpoint genes that have the potential to influence the progression of Leishmania infection. To achieve this, we exploited prior, curated knowledge from major databases and constructed 16 datasets of human molecular information consisting of coding genes and corresponding proteins. We obtained over 400 proteins, identifying approximately 200 genes. The proteins coded by these genes were subsequently used to build a network of protein–protein interactions, which enabled the identification of key players; we named this set Predicted Genes. Then, we selected approximately 10% of Predicted Genes for biological validation. THP-1 cells, a line of human macrophages, were infected with Leishmania major in vitro for the validation process. We observed that L. major has the capacity to impact crucial genes involved in the immune response, resulting in macrophage inactivation and creating a conducive environment for the survival of Leishmania parasites.

Early detection of prediabetes is crucial to preventing its progression to diabetes. Providing individuals with a personalized sense of their risk could improve prevention efforts. While complex mathematical models that simulate metabolic and inflammatory processes offer detailed and patient-specific insights, their computational cost usually makes them impractical for real-time prediction on mobile platforms. This work introduces a long short-term memory (LSTM) surrogate for the MT2D model, that simulates the main metabolic and inflammatory processes undergoing the transition to prediabetes. The model is developed using a dataset of 43 669 simulated subjects, each with lifestyle inputs and biomarker outputs over six months. Using 8 time series inputs, the surrogate predicts the dynamics of 11 key metabolic and inflammatory outputs, closely replicating the behaviour of the MT2D model. After training, the proposed LSTM model reduces computational time from an average of 8.4 hours to 0.1 seconds per simulation, making it suitable for mobile device deployment. The model achieves root mean squared errors on the order of 10-2 on scaled data, and shows promise for prediabetes risk assessment by capturing trends in inflammatory biomarkers. This surrogate model can provide real-time and patient-specific insights into the metabolic health, potentially improving the understanding of prediabetes risk.

This contribution outlines current research aimed at developing models for personalized type 2 diabetes mellitus (T2D) prevention in the framework of the European project PRAESIIDIUM (Physics Informed Machine Learn-ing-Based Prediction and Reversion of Impaired Fasting Glucose Management) aimed at building a digital twin for preventing T2D in patients at risk. Specifically, the modelling approaches include both a multiscale, hybrid computational model of the human metaflammatory (metabolic and inflammatory) status, and data-driven models of the risk of developing T2D able to generate personalized recommendations for mitigating the individ-ual risk. The prediction algorithm will draw on a rich set of information for training, derived from prior clinical data, the individual's family history, and prospective clinical trials including clinical variables, wearable sensors, and a tracking mobile app (for diet, physical activity, and lifestyle). The models developed within the project will be the basis for building a platform for healthcare professionals and patients to estimate and monitor the indi-vidual risk of T2D in real time, thus potentially supporting personalized prevention and patient engagement.

Regular physical exercise and appropriate nutrition affect metabolic and hormonal responses and may reduce the risk of developing chronic non-communicable diseases such as high blood pressure, ischemic stroke, coronary heart disease, some types of cancer, and type 2 diabetes mellitus. Computational models describing the metabolic and hormonal changes due to the synergistic action of exercise and meal intake are, to date, scarce and mostly focussed on glucose absorption, ignoring the contribution of the other macronutrients. We here describe a model of nutrient intake, stomach emptying, and absorption of macronutrients in the gastrointestinal tract during and after the ingestion of a mixed meal, including the contribution of proteins and fats. We integrated this effort to our previous work in which we modeled the effects of a bout of physical exercise on metabolic homeostasis. We validated the computational model with reliable data from the literature. The simulations are overall physiologically consistent and helpful in describing the metabolic changes due to everyday life stimuli such as multiple mixed meals and variable periods of physical exercise over prolonged periods of time. This computational model may be used to design virtual cohorts of subjects differing in sex, age, height, weight, and fitness status, for specialized in silico challenge studies aimed at designing exercise and nutrition schemes to support health.

Assessing the validity of a psychometric test is fundamental to ensure a reliable interpretation of its outcomes. Few attempts have been made recently to complement classical approaches (e.g., factor models) with a novel technique based on network analysis. The objective of the current study is to carry out a network-based validation of the Eating Disorder Inventory 3 (EDI-3), a questionnaire designed for the assessment of eating disorders. Exploiting a reliable, open source sample of 1206 patients diagnosed with an eating disorder, we set up a robust validation process encompassing detection and handling of redundant EDI-3 items, estimation of the cross-sample psychometric network, resampling bootstrap procedure and computation of the median network of the replica samples. We then employed a community detection algorithm to identify the topological clusters, evaluated their coherence with the EDI-3 subscales and replicated the full validation analysis on the subpopulations corresponding to patients diagnosed with either anorexia nervosa or bulimia nervosa. Results of the network-based analysis, and particularly the topological community structures, provided support for almost all the composite scores of the EDI-3 and for 2 single subscales: Bulimia and Maturity Fear. A moderate instability of some dimensions led to the identification of a few multidimensional items that should be better located in the intersection of multiple psychological scales. We also found that, besides symptoms typically attributed to eating disorders, such as drive for thinness, also non-specific symptoms like low self-esteem and interoceptive deficits play a central role in both the cross-sample and the diagnosis-specific networks. Our work adds insights into the complex and multidimensional structure of EDI-3 by providing support to its network-based validity on both mixed and diagnosis-specific samples. Moreover, we replicated previous results that reinforce the transdiagnostic theory of eating disorders.

Motivation: Gene-disease associations are fundamental for understanding disease etiology and developing effective interventions and treatments. Identifying genes not yet associated with a disease due to a lack of studies is a challenging task in which prioritization based on prior knowledge is an important element. The computational search for new candidate disease genes may be eased by positive-unlabeled learning, the machine learning setting in which only a subset of instances are labeled as positive while the rest of the data set is unlabeled. In this work, we propose a set of effective network-based features to be used in a novel Markov diffusion-based multi-class labeling strategy for putative disease gene discovery. Results: The performances of the new labeling algorithm and the effectiveness of the proposed features have been tested on ten different disease data sets using three machine learning algorithms. The new features have been compared against classical topological and functional/ontological features and a set of network- and biological-derived features already used in gene discovery tasks. The predictive power of the integrated methodology in searching for new disease genes has been found to be competitive against state-of-the-art algorithms.Availability and implementation: The source code of NIAPU can be accessed at https://github. com/AndMastro/NIAPU. The source data used in this study are available online on the respective websites.

The importance of the immune system (IS) in tuberculosis (TB) drug development is often underestimated because of the intricate nature of experiments and the specialized knowledge needed. In vitro and animal studies fall short in replicating the intricate reactions of the human IS to drugs and infections. In this study, we present our initial efforts in employing an in silico approach to comprehend how an individual’s IS impacts the efficacy of therapy, particularly in managing mycobacterium tuberculosis (Mtb) infection and minimizing the risk of relapse. We employed a well-established agent-based IS simulator called C-IMMSIM. We conducted simulations to investigate the long-term outcomes of TB disease in a virtual cohort infected with Mtb over a 50-year period. Our simulations revealed that individuals with competent IS showed a high success rate in containing Mtb infection. Furthermore, to better understand the dynamic interactions between Mtb and the IS, we deliberately introduced specific IS deficiencies, thus successfully inducing short-term relapses and mortality. These results confirm the model’s ability to elucidate the mechanisms underlying the interactions between Mtb and the IS.

BACKGROUND: Network science represents a powerful and increasingly promising method for studying complex real-world problems. In the last decade, it has been applied to psychometric data in the attempt to explain psychopathologies as complex systems of causally interconnected symptoms. One category of mental disorders, relevant for their severity, incidence and multifaceted structure, is that of eating disorders (EDs), serious disturbances that negatively affect a person's eating behavior. AIMS: We aimed to review the corpus of psychometric network analysis methods by scrutinizing a large sample of network-based studies that exploit psychometric data related to EDs. A particular focus is given to the description of the methodologies for network estimation, network description and network stability analysis providing also a review of the statistical software packages currently used to carry out each phase of the network estimation and analysis workflow. Moreover, we try to highlight aspects with potential clinical impact such as core symptoms, influences of external factors, comorbidities, and related changes in network structure and connectivity across both time and subpopulations. METHODS: A systematic search was conducted (February 2022) on three different literature databases to identify 57 relevant research articles. The exclusion criteria comprehended studies not based on psychometric data, studies not using network analysis, studies with different aims or not focused on ED, and review articles. RESULTS: Almost all the selected 57 papers employed the same analytical procedures implemented in a collection of R packages specifically designed for psychometric network analysis and are mostly based on cross-sectional data retrieved from structured psychometric questionnaires, with just few exemptions of panel data. Most of them used the same techniques for all phases of their analysis. In particular, a pervasive use of the Gaussian Graphical Model with LASSO regularization was registered for in network estimation step. Among the clinically relevant results, we can include the fact that all papers found strong symptom interconnections between specific and nonspecific ED symptoms, suggesting that both types should therefore be addressed by clinical treatment. CONCLUSIONS: We here presented the largest and most comprehensive review to date about psychometric network analysis methods. Although these methods still need solid validation in the clinical setting, they have already been able to show many strengths and important results, as well as great potentials and perspectives, which have been analyzed here to provide suggestions on their use and their possible improvement.

The possibility to computationally prioritize candi- date disease genes capitalizing on existing information has led to a speedup in the discovery of new methods. Many gene discovery techniques exploit network data, like protein-protein interactions (PPIs), in order to extract knowledge from the network structure relying on several network metrics. We here present PROCONSUL, a method that builds on top of the concept of connectivity significance (CS) and exploits the idea of probabilistic exploration of the space of putative disease genes. We show that our methodology is able to outperform the state-of- the-art tool based on CS in several settings, and propose different, effective gene discovery strategies according to specific disease network properties.

The importance of faster drug development has never been more evident than in present time when the whole world is struggling to cope up with the COVID-19 pandemic. At times when timely development of effective drugs and treatment plans could potentially save millions of lives, drug repurposing is one area of medicine that has garnered much of research interest. Apart from experimental drug repurposing studies that happen within wet labs, lot many new quantitative methods have been proposed in the literature. In this paper, one such quantitative methods for drug repurposing is implemented and evaluated. DruSiLa (DRUg in-SIlico LAboratory) is an in-silico drug re- purposing method that leverages disease similarity measures to quantitatively rank existing drugs for their potential therapeutic efficacy against novel diseases. The proposed method makes use of available, manually curated, and open datasets on diseases, their genetic origins, and disease-related patho-phenotypes. DruSiLa evaluates pairwise disease similarity scores of any given target disease to each known disease in our dataset. Such similarity scores are then propagated through disease-drug associations, and aggregated at drug nodes to rank them for their predicted effectiveness against the target disease.

The traditional approach in medicine starts with investigating patients' symptoms to make a diagnosis. While with the advent of precision medicine, a diagnosis results from several factors that interact and need to be analyzed together. This added complexity asks for increased support for medical personnel in analyzing these data altogether. Our objective is to merge the traditional approach with network medicine to offer a tool to investigate together symptoms, anatomies, diseases, and genes to establish a diagnosis from different points of view. This paper aims to help the clinician with the typical workflow of disease analysis, proposing a Visual Analytics tool to ease this task. A use case demonstrates the benefits of the proposed solution.

Drug repurposing is a highly active research area, aiming at finding novel uses for drugs that have been previously developed for other therapeutic purposes. Despite the flourishing of methodologies, success is still partial, and different approaches offer, each, peculiar advantages. In this composite landscape, we present a novel methodology focusing on an efficient mathematical procedure based on gene similarity scores and biased random walks which rely on robust drug-gene-disease association data sets. The recommendation mechanism is further unveiled by means of the Markov chain underlying the random walk process, hence providing explainability about how findings are suggested. Performances evaluation and the analysis of a case study on rheumatoid arthritis show that our approach is accurate in providing useful recommendations and is computationally efficient, compared to the state of the art of drug repurposing approaches.

Primary biliary cholangitis (PBC) is a chronic, cholestatic, immune-mediated, and progressive liver disorder. Treatment to preventing the disease from advancing into later and irreversible stages is still an unmet clinical need. Accordingly, we set up a drug repurposing framework to find potential therapeutic agents targeting relevant pathways derived from an expanded pool of genes involved in different stages of PBC. Starting with updated human protein–protein interaction data and genes specifically involved in the early and late stages of PBC, a network medicine approach was used to provide a PBC “proximity” or “involvement” gene ranking using network diffusion algorithms and machine learning models. The top genes in the proximity ranking, when combined with the original PBC-related genes, resulted in a final dataset of the genes most involved in PBC disease. Finally, a drug repurposing strategy was implemented by mining and utilizing dedicated drug–gene interaction and druggable genome information knowledge bases (e.g., the DrugBank repository). We identified several potential drug candidates interacting with PBC pathways after performing an over-representation analysis on our initial 1121-seed gene list and the resulting disease-associated (algorithm-obtained) genes. The mechanism and potential therapeutic applications of such drugs were then thoroughly discussed, with a particular emphasis on different stages of PBC disease. We found that interleukin/EGFR/TNF-alpha inhibitors, branched-chain amino acids, geldanamycin, tauroursodeoxycholic acid, genistein, antioestrogens, curcumin, antineovascularisation agents, enzyme/protease inhibitors, and antirheumatic agents are promising drugs targeting distinct stages of PBC. We developed robust and transparent selection mechanisms for prioritizing already approved medicinal products or investigational products for repurposing based on recognized unmet medical needs in PBC, as well as solid preliminary data to achieve this goal.

Despite the international guidelines on the containment of the coronavirus disease 2019 (COVID-19) pandemic, the European scientific community was not sufficiently prepared to coordinate scientific efforts. To improve preparedness for future pandemics, we have initiated a network of nine European-funded Cooperation in Science and Technology (COST) Actions that can help facilitate inter-, multi-, and trans-disciplinary communication and collaboration.

Motivation Inflammation is part of the complex function that addresses harmful stimuli, and the first phase of wound healing (WH), which guarantees living systems' homeostasis. Deviances from physiology make inflammation turn acute (sepsis, 11M death/y) or chronic (non-communicable diseases, 41M death/y). Therefore, tackling inflammation is a key priority. We recently proposed (Maturo et al., 2020) to revise the conventional inflammatory pathway (innate immune response) to include WH (expanded inflammatory pathway). Methods We manually identified the Reactome pathways that include all reactions and species relevant to WH. Cytoscape was then used to perform the union of the SBML converted pathways, with the largest connected component being retained (732 nodes, 13.944 edges). The same was done for the innate immune response (R-HSA-168249.8) with 487 nodes, 11.744 edges. We then focused on: NF-kB (fundamental hub in all inflammatory reactions), TNF-? (renown target of inflammatory diseases) and RAC1 (key player in mechanotransduction events of WH). Results Preliminary topological results highlight the stability of closeness centrality, i.e. all molecules preserve their efficiency in spreading information. Conversely, betweenness centrality is stable for NF-kB (0.068), confirming NF-kB relevance, while halving its (very low) value in the expanded pathway for TNF-? (from 2.85E-06 to 1.29E-06). This indicates that the ability to bridge different parts of the graphs is less effective if we consider inflammation as an expanded concept, possibly contributing to explain the many side effects of anti-TNF-? therapies. Interestingly, RAC1 presents stable betweenness (from 0.094 to 0.093), comparable to NF-kB, supporting the hypothesis that WH-leveraging therapies could act on a relevant and stable target, so far neglected (Nardini et al., 2016).

Aggregating transcriptomics data across hospitals can increase sensitivity and robustness of differential expression analyses, yielding deeper clinical insights. As data exchange is often restricted by privacy legislation, meta-analyses are frequently employed to pool local results. However, the accuracy might drop if class labels are inhomogeneously distributed among cohorts. Flimma (https://exbio.wzw.tum.de/flimma/) addresses this issue by implementing the state-of-the-art workflow limma voom in a federated manner, i.e., patient data never leaves its source site. Flimma results are identical to those generated by limma voom on aggregated datasets even in imbalanced scenarios where meta-analysis approaches fail.

Background: Systems Medicine is a novel approach to medicine, i.e. an interdisciplinary field that considers the human body as a system, composed of multiple parts and of complex relationships at multiple levels, and further integrated into an environment. Exploring Systems Medicine implies understanding and combining concepts coming from diametral different fields, including medicine, biology, statistics, modelling and simulation, and data science. Such heterogeneity leads to semantic issues, which may slow down implementation and fruitful interaction between these highly diverse fields. Methods: In this review we collect and explain over one hundred terms related to Systems Medicine. These include both modelling and data science terms and basic systems medicine terms, along with some synthetic definitions, examples of applications, and lists of relevant references. Results: This glossary aims at being a first aid kit for the Systems Medicine researcher facing an unfamiliar term, where he/she can get a first understanding of them, and, more importantly, examples and references for keep digging into the topic.

Drug research, therapy development, and other areas of pharmacology and medicine can benefit from simula- tions and optimization of mathematical models that contain a mathematical description of interactions between systems elements at the cellular, tissue, organ, body, and population level. This approach is the foundation of systems medicine and precision medicine. Here, simulated experiments are performed with computers (in silico) first, and they are then replicated through lab experiments (in vivo or in vitro) or clinical studies. In turn, these experiments and studies can be used to validate or improve the models. This iterative loop of dry and wet lab work is successful when biomedical researchers tightly collaborate with data scientists and modelers. From an educational point of view, the interdisciplinary research in systems biology can be sustained most ef- fectively when specialists have been trained to have both a strong background in the disciplines of biology or modeling and strong communication skills, which make them able to communicate with other specialists. This overview addresses possible interdisciplinary communication gaps. Focusing our attention on biomedical re- searchers, we describe the reasons for using modeling and ways to collaborate with modelers, including their needs for specific biological expertise and data. This review includes an introduction to the principles of several widely used mechanistic modeling methods, focusing on their areas of applicability as well as their limitations. A potential complementary role of machine-learning methods in the development of mechanistic models is also discussed. The descriptions of the methods also include links to corresponding modeling software tools as well as practical examples of their application. Finally, we also explicitly address different aspects of multiscale mod- eling approaches that allow a more complete and holistic perspective of the human body.