An overview of bioinformatics courses delivered at the academic level in Italy: Reflections and recommendations from BITS.

In Italian universities, bioinformatics courses are increasingly being incorporated into different study paths. However, the content of bioinformatics courses is usually selected by the professor teaching the course, in the absence of national guidelines that identify the minimum indispensable knowledge in bioinformatics that undergraduate students from different scientific fields should achieve. The Training&Teaching group of the Bioinformatics Italian Society (BITS) proposed to university professors a survey aimed at portraying the current situation of bioinformatics courses within undergraduate curricula in Italy (i.e., bioinformatics courses activated within both bachelor's and master's degrees). Furthermore, the Training&Teaching group took a cue from the survey outcomes to develop recommendations for the design and the inclusion of bioinformatics courses in academic curricula. Here, we present the outcomes of the survey, as well as the BITS recommendations, with the hope that they may support BITS members in identifying learning outcomes and selecting content for their bioinformatics courses. As we share our effort with the broader international community involved in teaching bioinformatics at academic level, we seek feedback and thoughts on our proposal and hope to start a fruitful debate on the topic, including how to better fulfill the real bioinformatics knowledge needs of the research and the labor market at both the national and international level.

A framework for validating AI in precision medicine: considerations from the European ITFoC consortium.

BACKGROUND: Artificial intelligence (AI) has the potential to transform our healthcare systems significantly. New AI technologies based on machine learning approaches should play a key role in clinical decision-making in the future. However, their implementation in health care settings remains limited, mostly due to a lack of robust validation procedures. There is a need to develop reliable assessment frameworks for the clinical validation of AI. We present here an approach for assessing AI for predicting treatment response in triple-negative breast cancer (TNBC), using real-world data and molecular -omics data from clinical data warehouses and biobanks. METHODS: The European "ITFoC (Information Technology for the Future Of Cancer)" consortium designed a framework for the clinical validation of AI technologies for predicting treatment response in oncology. RESULTS: This framework is based on seven key steps specifying: (1) the intended use of AI, (2) the target population, (3) the timing of AI evaluation, (4) the datasets used for evaluation, (5) the procedures used for ensuring data safety (including data quality, privacy and security), (6) the metrics used for measuring performance, and (7) the procedures used to ensure that the AI is explainable. This framework forms the basis of a validation platform that we are building for the "ITFoC Challenge". This community-wide competition will make it possible to assess and compare AI algorithms for predicting the response to TNBC treatments with external real-world datasets. CONCLUSIONS: The predictive performance and safety of AI technologies must be assessed in a robust, unbiased and transparent manner before their implementation in healthcare settings. We believe that the consideration of the ITFoC consortium will contribute to the safe transfer and implementation of AI in clinical settings, in the context of precision oncology and personalized care.

FiCoS: A fine-grained and coarse-grained GPU-powered deterministic simulator for biochemical networks.

Mathematical models of biochemical networks can largely facilitate the comprehension of the mechanisms at the basis of cellular processes, as well as the formulation of hypotheses that can be tested by means of targeted laboratory experiments. However, two issues might hamper the achievement of fruitful outcomes. On the one hand, detailed mechanistic models can involve hundreds or thousands of molecular species and their intermediate complexes, as well as hundreds or thousands of chemical reactions, a situation generally occurring in rule-based modeling. On the other hand, the computational analysis of a model typically requires the execution of a large number of simulations for its calibration, or to test the effect of perturbations. As a consequence, the computational capabilities of modern Central Processing Units can be easily overtaken, possibly making the modeling of biochemical networks a worthless or ineffective effort. To the aim of overcoming the limitations of the current state-of-the-art simulation approaches, we present in this paper FiCoS, a novel "black-box" deterministic simulator that effectively realizes both a fine-grained and a coarse-grained parallelization on Graphics Processing Units. In particular, FiCoS exploits two different integration methods, namely, the Dormand-Prince and the Radau IIA, to efficiently solve both non-stiff and stiff systems of coupled Ordinary Differential Equations. We tested the performance of FiCoS against different deterministic simulators, by considering models of increasing size and by running analyses with increasing computational demands. FiCoS was able to dramatically speedup the computations up to 855×, showing to be a promising solution for the simulation and analysis of large-scale models of complex biological processes.

A Low-Dose CT-Based Radiomic Model to Improve Characterization and Screening Recall Intervals of Indeterminate Prevalent Pulmonary Nodules.

Lung cancer (LC) is currently one of the main causes of cancer-related deaths worldwide. Low-dose computed tomography (LDCT) of the chest has been proven effective in secondary prevention (i.e., early detection) of LC by several trials. In this work, we investigated the potential impact of radiomics on indeterminate prevalent pulmonary nodule (PN) characterization and risk stratification in subjects undergoing LDCT-based LC screening. As a proof-of-concept for radiomic analyses, the first aim of our study was to assess whether indeterminate PNs could be automatically classified by an LDCT radiomic classifier as solid or sub-solid (first-level classification), and in particular for sub-solid lesions, as non-solid versus part-solid (second-level classification). The second aim of the study was to assess whether an LCDT radiomic classifier could automatically predict PN risk of malignancy, and thus optimize LDCT recall timing in screening programs. Model performance was evaluated using the area under the receiver operating characteristic curve (AUC), accuracy, positive predictive value, negative predictive value, sensitivity, and specificity. The experimental results showed that an LDCT radiomic machine learning classifier can achieve excellent performance for characterization of screen-detected PNs (mean AUC of 0.89 ± 0.02 and 0.80 ± 0.18 on the blinded test dataset for the first-level and second-level classifiers, respectively), providing quantitative information to support clinical management. Our study showed that a radiomic classifier could be used to optimize LDCT recall for indeterminate PNs. According to the performance of such a classifier on the blinded test dataset, within the first 6 months, 46% of the malignant PNs and 38% of the benign ones were identified, improving early detection of LC by doubling the current detection rate of malignant nodules from 23% to 46% at a low cost of false positives. In conclusion, we showed the high potential of LDCT-based radiomics for improving the characterization and optimizing screening recall intervals of indeterminate PNs.

HyperBeta: characterizing the structural dynamics of proteins and self-assembling peptides.

Self-assembling processes are ubiquitous phenomena that drive the organization and the hierarchical formation of complex molecular systems. The investigation of assembling dynamics, emerging from the interactions among biomolecules like amino-acids and polypeptides, is fundamental to determine how a mixture of simple objects can yield a complex structure at the nano-scale level. In this paper we present HyperBeta, a novel open-source software that exploits an innovative algorithm based on hyper-graphs to efficiently identify and graphically represent the dynamics of [Formula: see text]-sheets formation. Differently from the existing tools, HyperBeta directly manipulates data generated by means of coarse-grained molecular dynamics simulation tools (GROMACS), performed using the MARTINI force field. Coarse-grained molecular structures are visualized using HyperBeta 's proprietary real-time high-quality 3D engine, which provides a plethora of analysis tools and statistical information, controlled by means of an intuitive event-based graphical user interface. The high-quality renderer relies on a variety of visual cues to improve the readability and interpretability of distance and depth relationships between peptides. We show that HyperBeta is able to track the [Formula: see text]-sheets formation in coarse-grained molecular dynamics simulations, and provides a completely new and efficient mean for the investigation of the kinetics of these nano-structures. HyperBeta will therefore facilitate biotechnological and medical research where these structural elements play a crucial role, such as the development of novel high-performance biomaterials in tissue engineering, or a better comprehension of the molecular mechanisms at the basis of complex pathologies like Alzheimer's disease.

Surfing on Fitness Landscapes: A Boost on Optimization by Fourier Surrogate Modeling.

Surfing in rough waters is not always as fun as wave riding the "big one". Similarly, in optimization problems, fitness landscapes with a huge number of local optima make the search for the global optimum a hard and generally annoying game. Computational Intelligence optimization metaheuristics use a set of individuals that "surf" across the fitness landscape, sharing and exploiting pieces of information about local fitness values in a joint effort to find out the global optimum. In this context, we designed surF, a novel surrogate modeling technique that leverages the discrete Fourier transform to generate a smoother, and possibly easier to explore, fitness landscape. The rationale behind this idea is that filtering out the high frequencies of the fitness function and keeping only its partial information (i.e., the low frequencies) can actually be beneficial in the optimization process. We prove our theory by combining surF with a settings free variant of Particle Swarm Optimization (PSO) based on Fuzzy Logic, called Fuzzy Self-Tuning PSO. Specifically, we introduce a new algorithm, named F3ST-PSO, which performs a preliminary exploration on the surrogate model followed by a second optimization using the actual fitness function. We show that F3ST-PSO can lead to improved performances, notably using the same budget of fitness evaluations.

cuProCell: GPU-Accelerated Analysis of Cell Proliferation With Flow Cytometry Data.

The investigation of cell proliferation can provide useful insights for the comprehension of cancer progression, resistance to chemotherapy and relapse. To this aim, computational methods and experimental measurements based on in vivo label-retaining assays can be coupled to explore the dynamic behavior of tumoral cells. ProCell is a software that exploits flow cytometry data to model and simulate the kinetics of fluorescence loss that is due to stochastic events of cell division. Since the rate of cell division is not known, ProCell embeds a calibration process that might require thousands of stochastic simulations to properly infer the parameterization of cell proliferation models. To mitigate the high computational costs, in this paper we introduce a parallel implementation of ProCell's simulation algorithm, named cuProCell, which leverages Graphics Processing Units (GPUs). Dynamic Parallelism was used to efficiently manage the cell duplication events, in a radically different way with respect to common computing architectures. We present the advantages of cuProCell for the analysis of different models of cell proliferation in Acute Myeloid Leukemia (AML), using data collected from the spleen of human xenografts in mice. We show that, by exploiting GPUs, our method is able to not only automatically infer the models' parameterization, but it is also 237× faster than the sequential implementation. This study highlights the presence of a relevant percentage of quiescent and potentially chemoresistant cells in AML in vivo, and suggests that maintaining a dynamic equilibrium among the different proliferating cell populations might play an important role in disease progression.

MaREA4Galaxy: Metabolic reaction enrichment analysis and visualization of RNA-seq data within Galaxy.

We present MaREA4Galaxy, a user-friendly tool that allows a user to characterize and to graphically compare groups of samples with different transcriptional regulation of metabolism, as estimated from cross-sectional RNA-seq data. The tool is available as plug-in for the widely-used Galaxy platform for comparative genomics and bioinformatics analyses. MaREA4Galaxy combines three modules. The Expression2RAS module, which, for each reaction of a specified set, computes a Reaction Activity Score (RAS) as a function of the expression level of genes encoding for the associated enzyme. The MaREA (Metabolic Reaction Enrichment Analysis) module that allows to highlight significant differences in reaction activities between specified groups of samples. The Clustering module which employs the RAS computed before as a metric for unsupervised clustering of samples into distinct metabolic subgroups; the Clustering tool provides different clustering techniques and implements standard methods to evaluate the goodness of the results.

Single-cell Digital Twins for Cancer Preclinical Investigation.

Laboratory models derived from clinical samples represent a solid platform in preclinical research for drug testing and investigation of disease mechanisms. The integration of these laboratory models with their digital counterparts (i.e., predictive mathematical models) allows to set up digital twins essential to fully exploit their potential to face the enormous molecular complexity of human organisms. In particular, due to the close integration of cell metabolism with all other cellular processes, any perturbation in cellular physiology typically reflect on altered cells metabolic profiling. In this regard, changes in metabolism have been shown, also in our laboratory, to drive a causal role in the emergence of cancer disease. Nevertheless, a unique metabolic program does not describe the altered metabolic profile of all tumour cells due to many causes from genetic variability to intratumour heterogeneous dependency on nutrients consumption and metabolism by multiple co-existing subclones. Currently, fluxomics approaches just match with the necessity of characterizing the overall flux distribution of cells within given samples, by disregarding possible heterogeneous behaviors. For the purpose of stratifying cancer heterogeneous subpopulations, quantification of fluxes at the single-cell level is needed. To this aim, we here present a new computational framework called single-cell Flux Balance Analysis (scFBA) that aims to set up digital metabolic twins in the perspective of being better exploited within a framework that makes also use of laboratory patient cell models. In particular, scFBA aims at integrating single-cell RNA-seq data within computational population models in order to depict a snapshot of the corresponding single-cell metabolic phenotypes at a given moment, together with an unsupervised identification of metabolic subpopulations.

ACDC: Automated Cell Detection and Counting for Time-Lapse Fluorescence Microscopy.

Advances in microscopy imaging technologies have enabled the visualization of live-cell dynamic processes using time-lapse microscopy imaging. However, modern methods exhibit several limitations related to the training phases and to time constraints, hindering their application in the laboratory practice. In this work, we present a novel method, named Automated Cell Detection and Counting (ACDC), designed for activity detection of fluorescent labeled cell nuclei in time-lapse microscopy. ACDC overcomes the limitations of the literature methods, by first applying bilateral filtering on the original image to smooth the input cell images while preserving edge sharpness, and then by exploiting the watershed transform and morphological filtering. Moreover, ACDC represents a feasible solution for the laboratory practice, as it can leverage multi-core architectures in computer clusters to efficiently handle large-scale imaging datasets. Indeed, our Parent-Workers implementation of ACDC allows to obtain up to a 3.7× speed-up compared to the sequential counterpart. ACDC was tested on two distinct cell imaging datasets to assess its accuracy and effectiveness on images with different characteristics. We achieved an accurate cell-count and nuclei segmentation without relying on large-scale annotated datasets, a result confirmed by the average Dice Similarity Coefficients of 76.84 and 88.64 and the Pearson coefficients of 0.99 and 0.96, calculated against the manual cell counting, on the two tested datasets.

Fuzzy modeling and global optimization to predict novel therapeutic targets in cancer cells.

MOTIVATION: The elucidation of dysfunctional cellular processes that can induce the onset of a disease is a challenging issue from both the experimental and computational perspectives. Here we introduce a novel computational method based on the coupling between fuzzy logic modeling and a global optimization algorithm, whose aims are to (1) predict the emergent dynamical behaviors of highly heterogeneous systems in unperturbed and perturbed conditions, regardless of the availability of quantitative parameters, and (2) determine a minimal set of system components whose perturbation can lead to a desired system response, therefore facilitating the design of a more appropriate experimental strategy. RESULTS: We applied this method to investigate what drives K-ras-induced cancer cells, displaying the typical Warburg effect, to death or survival upon progressive glucose depletion. The optimization analysis allowed to identify new combinations of stimuli that maximize pro-apoptotic processes. Namely, our results provide different evidences of an important protective role for protein kinase A in cancer cells under several cellular stress conditions mimicking tumor behavior. The predictive power of this method could facilitate the assessment of the response of other complex heterogeneous systems to drugs or mutations in fields as medicine and pharmacology, therefore paving the way for the development of novel therapeutic treatments. AVAILABILITY AND IMPLEMENTATION: The source code of FUMOSO is available under the GPL 2.0 license on GitHub at the following URL: https://github.com/aresio/FUMOSO. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Computational Methods for Resting-State EEG of Patients With Disorders of Consciousness.

Patients who survive brain injuries may develop Disorders of Consciousness (DOC) such as Coma, Vegetative State (VS) or Minimally Conscious State (MCS). Unfortunately, the rate of misdiagnosis between VS and MCS due to clinical judgment is high. Therefore, diagnostic decision support systems aiming to correct any differentiation between VS and MCS are essential for the characterization of an adequate treatment and an effective prognosis. In recent decades, there has been a growing interest in the new EEG computational techniques. We have reviewed how resting-state EEG is computationally analyzed to support differential diagnosis between VS and MCS in view of applicability of these methods in clinical practice. The studies available so far have used different techniques and analyses; it is therefore hard to draw general conclusions. Studies using a discriminant analysis with a combination of various factors and reporting a cut-off are among the most interesting ones for a future clinical application.

A novel framework for MR image segmentation and quantification by using MedGA.

BACKGROUND AND OBJECTIVES: Image segmentation represents one of the most challenging issues in medical image analysis to distinguish among different adjacent tissues in a body part. In this context, appropriate image pre-processing tools can improve the result accuracy achieved by computer-assisted segmentation methods. Taking into consideration images with a bimodal intensity distribution, image binarization can be used to classify the input pictorial data into two classes, given a threshold intensity value. Unfortunately, adaptive thresholding techniques for two-class segmentation work properly only for images characterized by bimodal histograms. We aim at overcoming these limitations and automatically determining a suitable optimal threshold for bimodal Magnetic Resonance (MR) images, by designing an intelligent image analysis framework tailored to effectively assist the physicians during their decision-making tasks. METHODS: In this work, we present a novel evolutionary framework for image enhancement, automatic global thresholding, and segmentation, which is here applied to different clinical scenarios involving bimodal MR image analysis: (i) uterine fibroid segmentation in MR guided Focused Ultrasound Surgery, and (ii) brain metastatic cancer segmentation in neuro-radiosurgery therapy. Our framework exploits MedGA as a pre-processing stage. MedGA is an image enhancement method based on Genetic Algorithms that improves the threshold selection, obtained by the efficient Iterative Optimal Threshold Selection algorithm, between the underlying sub-distributions in a nearly bimodal histogram. RESULTS: The results achieved by the proposed evolutionary framework were quantitatively evaluated, showing that the use of MedGA as a pre-processing stage outperforms the conventional image enhancement methods (i.e., histogram equalization, bi-histogram equalization, Gamma transformation, and sigmoid transformation), in terms of both MR image enhancement and segmentation evaluation metrics. CONCLUSIONS: Thanks to this framework, MR image segmentation accuracy is considerably increased, allowing for measurement repeatability in clinical workflows. The proposed computational solution could be well-suited for other clinical contexts requiring MR image analysis and segmentation, aiming at providing useful insights for differential diagnosis and prognosis.

GenHap: a novel computational method based on genetic algorithms for haplotype assembly.

BACKGROUND: In order to fully characterize the genome of an individual, the reconstruction of the two distinct copies of each chromosome, called haplotypes, is essential. The computational problem of inferring the full haplotype of a cell starting from read sequencing data is known as haplotype assembly, and consists in assigning all heterozygous Single Nucleotide Polymorphisms (SNPs) to exactly one of the two chromosomes. Indeed, the knowledge of complete haplotypes is generally more informative than analyzing single SNPs and plays a fundamental role in many medical applications. RESULTS: To reconstruct the two haplotypes, we addressed the weighted Minimum Error Correction (wMEC) problem, which is a successful approach for haplotype assembly. This NP-hard problem consists in computing the two haplotypes that partition the sequencing reads into two disjoint sub-sets, with the least number of corrections to the SNP values. To this aim, we propose here GenHap, a novel computational method for haplotype assembly based on Genetic Algorithms, yielding optimal solutions by means of a global search process. In order to evaluate the effectiveness of our approach, we run GenHap on two synthetic (yet realistic) datasets, based on the Roche/454 and PacBio RS II sequencing technologies. We compared the performance of GenHap against HapCol, an efficient state-of-the-art algorithm for haplotype phasing. Our results show that GenHap always obtains high accuracy solutions (in terms of haplotype error rate), and is up to 4× faster than HapCol in the case of Roche/454 instances and up to 20× faster when compared on the PacBio RS II dataset. Finally, we assessed the performance of GenHap on two different real datasets. CONCLUSIONS: Future-generation sequencing technologies, producing longer reads with higher coverage, can highly benefit from GenHap, thanks to its capability of efficiently solving large instances of the haplotype assembly problem. Moreover, the optimization approach proposed in GenHap can be extended to the study of allele-specific genomic features, such as expression, methylation and chromatin conformation, by exploiting multi-objective optimization techniques. The source code and the full documentation are available at the following GitHub repository: https://github.com/andrea-tango/GenHap .

Integration of single-cell RNA-seq data into population models to characterize cancer metabolism.

Metabolic reprogramming is a general feature of cancer cells. Regrettably, the comprehensive quantification of metabolites in biological specimens does not promptly translate into knowledge on the utilization of metabolic pathways. By estimating fluxes across metabolic pathways, computational models hold the promise to bridge this gap between data and biological functionality. These models currently portray the average behavior of cell populations however, masking the inherent heterogeneity that is part and parcel of tumorigenesis as much as drug resistance. To remove this limitation, we propose single-cell Flux Balance Analysis (scFBA) as a computational framework to translate single-cell transcriptomes into single-cell fluxomes. We show that the integration of single-cell RNA-seq profiles of cells derived from lung adenocarcinoma and breast cancer patients into a multi-scale stoichiometric model of a cancer cell population: significantly 1) reduces the space of feasible single-cell fluxomes; 2) allows to identify clusters of cells with different growth rates within the population; 3) points out the possible metabolic interactions among cells via exchange of metabolites. The scFBA suite of MATLAB functions is available at https://github.com/BIMIB-DISCo/scFBA, as well as the case study datasets.

Modeling cell proliferation in human acute myeloid leukemia xenografts.

MOTIVATION: Acute myeloid leukemia (AML) is one of the most common hematological malignancies, characterized by high relapse and mortality rates. The inherent intra-tumor heterogeneity in AML is thought to play an important role in disease recurrence and resistance to chemotherapy. Although experimental protocols for cell proliferation studies are well established and widespread, they are not easily applicable to in vivo contexts, and the analysis of related time-series data is often complex to achieve. To overcome these limitations, model-driven approaches can be exploited to investigate different aspects of cell population dynamics. RESULTS: In this work, we present ProCell, a novel modeling and simulation framework to investigate cell proliferation dynamics that, differently from other approaches, takes into account the inherent stochasticity of cell division events. We apply ProCell to compare different models of cell proliferation in AML, notably leveraging experimental data derived from human xenografts in mice. ProCell is coupled with Fuzzy Self-Tuning Particle Swarm Optimization, a swarm-intelligence settings-free algorithm used to automatically infer the models parameterizations. Our results provide new insights on the intricate organization of AML cells with highly heterogeneous proliferative potential, highlighting the important role played by quiescent cells and proliferating cells characterized by different rates of division in the progression and evolution of the disease, thus hinting at the necessity to further characterize tumor cell subpopulations. AVAILABILITY AND IMPLEMENTATION: The source code of ProCell and the experimental data used in this work are available under the GPL 2.0 license on GITHUB at the following URL: https://github.com/aresio/ProCell. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Corrigendum: Computational Methods for Resting-State EEG of Patients With Disorders of Consciousness.

[This corrects the article DOI: 10.3389/fnins.2019.00807.].

Integration of transcriptomic data and metabolic networks in cancer samples reveals highly significant prognostic power.

Effective stratification of cancer patients on the basis of their molecular make-up is a key open challenge. Given the altered and heterogenous nature of cancer metabolism, we here propose to use the overall expression of central carbon metabolism as biomarker to characterize groups of patients with important characteristics, such as response to ad-hoc therapeutic strategies and survival expectancy. To this end, we here introduce the data integration framework named Metabolic Reaction Enrichment Analysis (MaREA), which strives to characterize the metabolic deregulations that distinguish cancer phenotypes, by projecting RNA-seq data onto metabolic networks, without requiring metabolic measurements. MaREA computes a score for each network reaction, based on the expression of the set of genes encoding for the associated enzyme(s). The scores are first used as features for cluster analysis and then to rank and visualize in an organized fashion the metabolic deregulations that distinguish cancer sub-types. We applied our method to recent lung and breast cancer RNA-seq datasets from The Cancer Genome Atlas and we were able to identify subgroups of patients with significant differences in survival expectancy. We show how the prognostic power of MaREA improves when an extracted and further curated core model focusing on central carbon metabolism is used rather than the genome-wide reference network. The visualization of the metabolic differences between the groups with best and worst prognosis allowed to identify and analyze key metabolic properties related to cancer aggressiveness. Some of these properties are shared across different cancer (sub) types, e.g., the up-regulation of nucleic acid and amino acid synthesis, whereas some other appear to be tumor-specific, such as the up- or down-regulation of the phosphoenolpyruvate carboxykinase reaction, which display different patterns in distinct tumor (sub)types. These results might be soon employed to deliver highly automated diagnostic and prognostic strategies for cancer patients.

Emerging ensembles of kinetic parameters to characterize observed metabolic phenotypes.

BACKGROUND: Determining the value of kinetic constants for a metabolic system in the exact physiological conditions is an extremely hard task. However, this kind of information is of pivotal relevance to effectively simulate a biological phenomenon as complex as metabolism. RESULTS: To overcome this issue, we propose to investigate emerging properties of ensembles of sets of kinetic constants leading to the biological readout observed in different experimental conditions. To this aim, we exploit information retrievable from constraint-based analyses (i.e. metabolic flux distributions at steady state) with the goal to generate feasible values for kinetic constants exploiting the mass action law. The sets retrieved from the previous step will be used to parametrize a mechanistic model whose simulation will be performed to reconstruct the dynamics of the system (until reaching the metabolic steady state) for each experimental condition. Every parametrization that is in accordance with the expected metabolic phenotype is collected in an ensemble whose features are analyzed to determine the emergence of properties of a phenotype. In this work we apply the proposed approach to identify ensembles of kinetic parameters for five metabolic phenotypes of E. Coli, by analyzing five different experimental conditions associated with the ECC2comp model recently published by Hädicke and collaborators. CONCLUSIONS: Our results suggest that the parameter values of just few reactions are responsible for the emergence of a metabolic phenotype. Notably, in contrast with constraint-based approaches such as Flux Balance Analysis, the methodology used in this paper does not require to assume that metabolism is optimizing towards a specific goal.

MTGO: PPI Network Analysis Via Topological and Functional Module Identification.

Protein-protein interaction (PPI) networks are viable tools to understand cell functions, disease machinery, and drug design/repositioning. Interpreting a PPI, however, it is a particularly challenging task because of network complexity. Several algorithms have been proposed for an automatic PPI interpretation, at first by solely considering the network topology, and later by integrating Gene Ontology (GO) terms as node similarity attributes. Here we present MTGO - Module detection via Topological information and GO knowledge, a novel functional module identification approach. MTGO let emerge the bimolecular machinery underpinning PPI networks by leveraging on both biological knowledge and topological properties. In particular, it directly exploits GO terms during the module assembling process, and labels each module with its best fit GO term, easing its functional interpretation. MTGO shows largely better results than other state of the art algorithms (including recent GO-based ones) when searching for small or sparse functional modules, while providing comparable or better results all other cases. MTGO correctly identifies molecular complexes and literature-consistent processes in an experimentally derived PPI network of Myocardial infarction. A software version of MTGO is available freely for non-commercial purposes at https://gitlab.com/d1vella/MTGO .