[Synchronies and asynchronies in the development of COVID-19 pandemic in Italy]. / Sincronie e asincronie negli sviluppi della pandemia di COVID-19 sul territorio.

BACKGROUND: the study of the possible determinants of the rise and fall of infections can be of great relevance, as was experienced during the COVID-19 pandemic. One of the methods to understand whether determinants are simultaneous or develop through contiguity between different areas is the study of the diagnostic replication index RDt among regions. OBJECTIVES: to introduce the analysis of RDt variability and the subsequent application of a recently introduced functional clustering method as highly useful procedures for recognizing the presence of clusters with similar trends in epidemic curves. DESIGN: within the considered period, trends in regional RDt are analyzed in detail over four different time intervals. SETTING AND PARTICIPANTS: to exemplify this methodology, the study of variability in the period from the end of 2021 to the beginning of 2022 may be of interest. MAIN OUTCOMES MEASURES: the variability in the regional RDt indices is assessed by means of the correlation coefficient weighted with respect to the populations of the individual regions. The clustering procedure is applied to the time series of absolute RDt values. RESULTS: it emerges that the periods of increasing variability in the RDt correspond to the initial growth or decrease in the number of infections, while functional clustering identifies macro-areas in which the epidemic curves have had similar trends. What caused contagions to increase seems to relate to a factor that is not specific to certain areas, with the contribution in some cases of a contagion dynamic between adjacent areas. CONCLUSIONS: the variability in the trend of regional diagnostic replication indices, which are calculated with only a few days delay, is a further indicator for the early detection of major changes in the trend of epidemic curves. The clustering of epidemic index curves may be useful to determine whether determinants act simultaneously or by contiguity between adjacent areas.

CREDO: a friendly Customizable, REproducible, DOcker file generator for bioinformatics applications.

BACKGROUND: The analysis of large and complex biological datasets in bioinformatics poses a significant challenge to achieving reproducible research outcomes due to inconsistencies and the lack of standardization in the analysis process. These issues can lead to discrepancies in results, undermining the credibility and impact of bioinformatics research and creating mistrust in the scientific process. To address these challenges, open science practices such as sharing data, code, and methods have been encouraged. RESULTS: CREDO, a Customizable, REproducible, DOcker file generator for bioinformatics applications, has been developed as a tool to moderate reproducibility issues by building and distributing docker containers with embedded bioinformatics tools. CREDO simplifies the process of generating Docker images, facilitating reproducibility and efficient research in bioinformatics. The crucial step in generating a Docker image is creating the Dockerfile, which requires incorporating heterogeneous packages and environments such as Bioconductor and Conda. CREDO stores all required package information and dependencies in a Github-compatible format to enhance Docker image reproducibility, allowing easy image creation from scratch. The user-friendly GUI and CREDO's ability to generate modular Docker images make it an ideal tool for life scientists to efficiently create Docker images. Overall, CREDO is a valuable tool for addressing reproducibility issues in bioinformatics research and promoting open science practices.

A new computational workflow to guide personalized drug therapy.

OBJECTIVE: Computational models are at the forefront of the pursuit of personalized medicine thanks to their descriptive and predictive abilities. In the presence of complex and heterogeneous data, patient stratification is a prerequisite for effective precision medicine, since disease development is often driven by individual variability and unpredictable environmental events. Herein, we present GreatNectorworkflow as a valuable tool for (i) the analysis and clustering of patient-derived longitudinal data, and (ii) the simulation of the resulting model of patient-specific disease dynamics. METHODS: GreatNectoris designed by combining an analytic strategy composed of CONNECTOR, a data-driven framework for the inspection of longitudinal data, and an unsupervised methodology to stratify the subjects with GreatMod, a quantitative modeling framework based on the Petri Net formalism and its generalizations. RESULTS: To illustrate GreatNectorcapabilities, we exploited longitudinal data of four immune cell populations collected from Multiple Sclerosis patients. Our main results report that the T-cell dynamics after alemtuzumab treatment separate non-responders versus responders patients, and the patients in the non-responders group are characterized by an increase of the Th17 concentration around 36 months. CONCLUSION: GreatNectoranalysis was able to stratify individual patients into three model meta-patients whose dynamics suggested insight into patient-tailored interventions.

CONNECTOR, fitting and clustering of longitudinal data to reveal a new risk stratification system.

MOTIVATION: The transition from evaluating a single time point to examining the entire dynamic evolution of a system is possible only in the presence of the proper framework. The strong variability of dynamic evolution makes the definition of an explanatory procedure for data fitting and clustering challenging. RESULTS: We developed CONNECTOR, a data-driven framework able to analyze and inspect longitudinal data in a straightforward and revealing way. When used to analyze tumor growth kinetics over time in 1599 patient-derived xenograft growth curves from ovarian and colorectal cancers, CONNECTOR allowed the aggregation of time-series data through an unsupervised approach in informative clusters. We give a new perspective of mechanism interpretation, specifically, we define novel model aggregations and we identify unanticipated molecular associations with response to clinically approved therapies. AVAILABILITY AND IMPLEMENTATION: CONNECTOR is freely available under GNU GPL license at https://qbioturin.github.io/connector and https://doi.org/10.17504/protocols.io.8epv56e74g1b/v1.

How the Competition for Cysteine May Promote Infection of SARS-CoV-2 by Triggering Oxidative Stress.

SARS-CoV-2 induces a broad range of clinical manifestations. Besides the main receptor, ACE2, other putative receptors and co-receptors have been described and could become genuinely relevant to explain the different tropism manifested by new variants. In this study, we propose a biochemical model envisaging the competition for cysteine as a key mechanism promoting the infection and the selection of host receptors. The SARS-CoV-2 infection produces ROS and triggers a massive biosynthesis of proteins rich in cysteine; if this amino acid becomes limiting, glutathione levels are depleted and cannot control oxidative stress. Hence, infection succeeds. A receptor should be recognized as a marker of suitable intracellular conditions, namely the full availability of amino acids except for low cysteine. First, we carried out a comparative investigation of SARS-CoV-2 proteins and human ACE2. Then, using hierarchical cluster protein analysis, we searched for similarities between all human proteins and spike produced by the latest variant, Omicron BA.1. We found 32 human proteins very close to spike in terms of amino acid content. Most of these potential SARS-CoV-2 receptors have less cysteine than spike. We suggest that these proteins could signal an intracellular shortage of cysteine, predicting a burst of oxidative stress when used as viral entry mediators.

Computational modeling of the immune response in multiple sclerosis using epimod framework.

BACKGROUND: Multiple Sclerosis (MS) represents nowadays in Europe the leading cause of non-traumatic disabilities in young adults, with more than 700,000 EU cases. Although huge strides have been made over the years, MS etiology remains partially unknown. Furthermore, the presence of various endogenous and exogenous factors can greatly influence the immune response of different individuals, making it difficult to study and understand the disease. This becomes more evident in a personalized-fashion when medical doctors have to choose the best therapy for patient well-being. In this optics, the use of stochastic models, capable of taking into consideration all the fluctuations due to unknown factors and individual variability, is highly advisable. RESULTS: We propose a new model to study the immune response in relapsing remitting MS (RRMS), the most common form of MS that is characterized by alternate episodes of symptom exacerbation (relapses) with periods of disease stability (remission). In this new model, both the peripheral lymph node/blood vessel and the central nervous system are explicitly represented. The model was created and analysed using Epimod, our recently developed general framework for modeling complex biological systems. Then the effectiveness of our model was shown by modeling the complex immunological mechanisms characterizing RRMS during its course and under the DAC administration. CONCLUSIONS: Simulation results have proven the ability of the model to reproduce in silico the immune T cell balance characterizing RRMS course and the DAC effects. Furthermore, they confirmed the importance of a timely intervention on the disease course.

Impacts of reopening strategies for COVID-19 epidemic: a modeling study in Piedmont region.

BACKGROUND: Severe acute respiratory syndrome coronavirus 2 (SARS-COV-2), the causative agent of the coronavirus disease 19 (COVID-19), is a highly transmittable virus. Since the first person-to-person transmission of SARS-CoV-2 was reported in Italy on February 21st, 2020, the number of people infected with SARS-COV-2 increased rapidly, mainly in northern Italian regions, including Piedmont. A strict lockdown was imposed on March 21st until May 4th when a gradual relaxation of the restrictions started. In this context, computational models and computer simulations are one of the available research tools that epidemiologists can exploit to understand the spread of the diseases and to evaluate social measures to counteract, mitigate or delay the spread of the epidemic. METHODS: This study presents an extended version of the Susceptible-Exposed-Infected-Removed-Susceptible (SEIRS) model accounting for population age structure. The infectious population is divided into three sub-groups: (i) undetected infected individuals, (ii) quarantined infected individuals and (iii) hospitalized infected individuals. Moreover, the strength of the government restriction measures and the related population response to these are explicitly represented in the model. RESULTS: The proposed model allows us to investigate different scenarios of the COVID-19 spread in Piedmont and the implementation of different infection-control measures and testing approaches. The results show that the implemented control measures have proven effective in containing the epidemic, mitigating the potential dangerous impact of a large proportion of undetected cases. We also forecast the optimal combination of individual-level measures and community surveillance to contain the new wave of COVID-19 spread after the re-opening work and social activities. CONCLUSIONS: Our model is an effective tool useful to investigate different scenarios and to inform policy makers about the potential impact of different control strategies. This will be crucial in the upcoming months, when very critical decisions about easing control measures will need to be taken.

A computational framework for modeling and studying pertussis epidemiology and vaccination.

BACKGROUND: Emerging and re-emerging infectious diseases such as Zika, SARS, ncovid19 and Pertussis, pose a compelling challenge for epidemiologists due to their significant impact on global public health. In this context, computational models and computer simulations are one of the available research tools that epidemiologists can exploit to better understand the spreading characteristics of these diseases and to decide on vaccination policies, human interaction controls, and other social measures to counter, mitigate or simply delay the spread of the infectious diseases. Nevertheless, the construction of mathematical models for these diseases and their solutions remain a challenging tasks due to the fact that little effort has been devoted to the definition of a general framework easily accessible even by researchers without advanced modelling and mathematical skills. RESULTS: In this paper we describe a new general modeling framework to study epidemiological systems, whose novelties and strengths are: (1) the use of a graphical formalism to simplify the model creation phase; (2) the implementation of an R package providing a friendly interface to access the analysis techniques implemented in the framework; (3) a high level of portability and reproducibility granted by the containerization of all analysis techniques implemented in the framework; (4) a well-defined schema and related infrastructure to allow users to easily integrate their own analysis workflow in the framework. Then, the effectiveness of this framework is showed through a case of study in which we investigate the pertussis epidemiology in Italy. CONCLUSIONS: We propose a new general modeling framework for the analysis of epidemiological systems, which exploits Petri Net graphical formalism, R environment, and Docker containerization to derive a tool easily accessible by any researcher even without advanced mathematical and computational skills. Moreover, the framework was implemented following the guidelines defined by Reproducible Bioinformatics Project so it guarantees reproducible analysis and makes simple the developed of new user-defined workflows.

A computational approach based on the colored Petri net formalism for studying multiple sclerosis.

BACKGROUND: Multiple Sclerosis (MS) is an immune-mediated inflammatory disease of the Central Nervous System (CNS) which damages the myelin sheath enveloping nerve cells thus causing severe physical disability in patients. Relapsing Remitting Multiple Sclerosis (RRMS) is one of the most common form of MS in adults and is characterized by a series of neurologic symptoms, followed by periods of remission. Recently, many treatments were proposed and studied to contrast the RRMS progression. Among these drugs, daclizumab (commercial name Zinbryta), an antibody tailored against the Interleukin-2 receptor of T cells, exhibited promising results, but its efficacy was accompanied by an increased frequency of serious adverse events. Manifested side effects consisted of infections, encephalitis, and liver damages. Therefore daclizumab has been withdrawn from the market worldwide. Another interesting case of RRMS regards its progression in pregnant women where a smaller incidence of relapses until the delivery has been observed. RESULTS: In this paper we propose a new methodology for studying RRMS, which we implemented in GreatSPN, a state-of-the-art open-source suite for modelling and analyzing complex systems through the Petri Net (PN) formalism. This methodology exploits: (a) an extended Colored PN formalism to provide a compact graphical description of the system and to automatically derive a set of ODEs encoding the system dynamics and (b) the Latin Hypercube Sampling with PRCC index to calibrate ODE parameters for reproducing the real behaviours in healthy and MS subjects.To show the effectiveness of such methodology a model of RRMS has been constructed and studied. Two different scenarios of RRMS were thus considered. In the former scenario the effect of the daclizumab administration is investigated, while in the latter one RRMS was studied in pregnant women. CONCLUSIONS: We propose a new computational methodology to study RRMS disease. Moreover, we show that model generated and calibrated according to this methodology is able to reproduce the expected behaviours.