
Benedetto Intrigila, Igor Melatti, Alberto Tofani, and Guido Macchiarelli. "Computational models of myocardial endomysial collagen arrangement." Computer Methods and Programs in Biomedicine 86, no. 3 (2007): 232–244. Elsevier NorthHolland, Inc.. ISSN: 01692607. DOI: 10.1016/j.cmpb.2007.03.004.
Abstract: Collagen extracellular matrix is one of the factors related to high passive stiffness of cardiac muscle. However, the architecture and the mechanical aspects of the cardiac collagen matrix are not completely known. In particular, endomysial collagen contribution to the passive mechanics of cardiac muscle as well as its micro anatomical arrangement is still a matter of debate. In order to investigate mechanical and structural properties of endomysial collagen, we consider two alternative computational models of some specific aspects of the cardiac muscle. These two models represent two different views of endomysial collagen distribution: (1) the traditional view and (2) a new view suggested by the data obtained from scanning electron microscopy (SEM) in NaOH macerated samples (a method for isolating collagen from the other tissue). We model the myocardial tissue as a net of spring elements representing the cardiomyocytes together with the endomysial collagen distribution. Each element is a viscous elastic spring, characterized by an elastic and a viscous constant. We connect these springs to imitate the interconnections between collagen fibers. Then we apply to the net of springs some external forces of suitable magnitude and direction, obtaining an extension of the net itself. In our setting, the ratio forces magnitude /net extension is intended to model the stress /strain ratio of a microscopical portion of the myocardial tissue. To solve the problem of the correct identification of the values of the different parameters involved, we use an artificial neural network approach. In particular, we use this technique to learn, given a distribution of external forces, the elastic constants of the springs needed to obtain a desired extension as an equilibrium position. Our experimental findings show that, in the model of collagen distribution structured according to the new view, a given stress /strain ratio (of the net of springs, in the sense specified above) is obtained with much smaller (w.r.t. the other model, corresponding to the traditional view) elasticity constants of the springs. This seems to indicate that by an appropriate structure, a given stiffness of the myocardial tissue can be obtained with endomysial collagen fibers of much smaller size.



S. Sinisi, V. Alimguzhin, T. Mancini, E. Tronci, and B. Leeners. "Complete populations of virtual patients for in silico clinical trials." Bioinformatics (2021): 1–8. ISSN: 13674803. DOI: 10.1093/bioinformatics/btaa1026.
Abstract: Modelbased approaches to safety and efficacy assessment of pharmacological drugs, treatment strategies, or medical devices (In Silico Clinical Trial, ISCT) aim to decrease time and cost for the needed experimentations, reduce animal and human testing, and enable precision medicine. Unfortunately, in presence of nonidentifiable models (e.g., reaction networks), parameter estimation is not enough to generate complete populations of Virtual Patient (VPs), i.e., populations guaranteed to show the entire spectrum of model behaviours (phenotypes), thus ensuring representativeness of the trial.We present methods and software based on global search driven by statistical model checking that, starting from a (nonidentifiable) quantitative model of the human physiology (plus drugs PK/PD) and suitable biological and medical knowledge elicited from experts, compute a population of VPs whose behaviours are representative of the whole spectrum of phenotypes entailed by the model (completeness) and pairwise distinguishable according to userprovided criteria. This enables full granularity control on the size of the population to employ in an ISCT, guaranteeing representativeness while avoiding overrepresentation of behaviours.We proved the effectiveness of our algorithm on a nonidentifiable ODEbased model of the female HypothalamicPituitaryGonadal axis, by generating a population of 4 830 264 VPs stratified into 7 levels (at different granularity of behaviours), and assessed its representativeness against 86 retrospective health records from Pfizer, Hannover Medical School and University Hospital of Lausanne. The datasets are respectively covered by our VPs within Average Normalised Mean Absolute Error of 15%, 20%, and 35% (90% of the latter dataset is covered within 20% error).



Ed Kuijpers, Luigi Carotenuto, Jean Cristophe Malapert, Daniela MarkovVetter, Igor Melatti, Andrea Orlandini, and Ranni Pinchuk. "Collaboration on ISS Experiment Data and Knowledge Representation." In Proc. of IAC 2012. Vol. D.5.11., 2012.



B. Leeners, T. Krueger, K. Geraedts, E. Tronci, T. Mancini, F. Ille, M. Egli, S. Roeblitz, D. Wunder, L. Saleh et al. "Cognitive function in association with high estradiol levels resulting from fertility treatment." Hormones and Behavior 130 (2021): 104951. ISSN: 0018506x. DOI: 10.1016/j.yhbeh.2021.104951.
Abstract: The putative association between hormones and cognitive performance is controversial. While there is evidence that estradiol plays a neuroprotective role, hormone treatment has not been shown to improve cognitive performance. Current research is flawed by the evaluation of combined hormonal effects throughout the menstrual cycle or in the menopausal transition. The stimulation phase of a fertility treatment offers a unique model to study the effect of estradiol on cognitive function. This quasiexperimental observational study is based on data from 44 women receiving IVF in Zurich, Switzerland. We assessed visuospatial working memory, attention, cognitive bias, and hormone levels at the beginning and at the end of the stimulation phase of ovarian superstimulation as part of a fertility treatment. In addition to interindividual differences, we examined intraindividual change over time (withinsubject effects). The substantial increases in estradiol levels resulting from fertility treatment did not relate to any considerable change in cognitive functioning. As the tests applied represent a broad variety of cognitive functions on different levels of complexity and with various brain regions involved, we can conclude that estradiol does not show a significant shortterm effect on cognitive function.
Keywords: Cognition, Estrogen, Estradiol, Fertility treatment, Attention, Cognitive bias



"Charme." In Lecture Notes in Computer Science, edited by D. Geist and E. Tronci. Vol. 2860. Springer, 2003. ISSN: 354020363X. DOI: 10.1007/b93958.



Giuseppe Della Penna, Benedetto Intrigila, Daniele Magazzeni, Igor Melatti, and Enrico Tronci. "CGMurphi: Automatic synthesis of numerical controllers for nonlinear hybrid systems." European Journal of Control 19, no. 1 (2013): 14–36. Elsevier NorthHolland, Inc.. ISSN: 09473580. DOI: 10.1016/j.ejcon.2013.02.001.



Federico Mari, and Enrico Tronci. "CEGAR Based Bounded Model Checking of Discrete Time Hybrid Systems." In Hybrid Systems: Computation and Control (HSCC 2007), edited by A. Bemporad, A. Bicchi and G. C. Buttazzo, 399–412. Lecture Notes in Computer Science 4416. Springer, 2007. DOI: 10.1007/9783540714934_32.
Abstract: Many hybrid systems can be conveniently modeled as Piecewise Affine Discrete Time Hybrid Systems PADTHS. As well known Bounded Model Checking (BMC) for such systems comes down to solve a Mixed Integer Linear Programming (MILP) feasibility problem. We present a SAT based BMC algorithm for automatic verification of PADTHSs. Using Counterexample Guided Abstraction Refinement (CEGAR) our algorithm gradually transforms a PADTHS verification problem into larger and larger SAT problems. Our experimental results show that our approach can handle PADTHSs that are more then 50 times larger than those that can be handled using a MILP solver.
Keywords: Model Checking, Abstraction, CEGAR, SAT, Hybrid Systems, DTHS



Giuseppe Della Penna, Benedetto Intrigila, Igor Melatti, Enrico Tronci, and Marisa Venturini Zilli. "Bounded Probabilistic Model Checking with the Mur$\varphi$ Verifier." In Formal Methods in ComputerAided Design, 5th International Conference, FMCAD 2004, Austin, Texas, USA, November 1517, 2004, Proceedings, edited by A. J. Hu and A. K. Martin, 214–229. Lecture Notes in Computer Science 3312. Springer, 2004. ISSN: 3540237380. DOI: 10.1007/9783540304944_16.
Abstract: In this paper we present an explicit verification algorithm for Probabilistic Systems defining discrete time/finite state Markov Chains. We restrict ourselves to verification of Bounded PCTL formulas (BPCTL), that is, PCTL formulas in which all Until operators are bounded, possibly with different bounds. This means that we consider only paths (system runs) of bounded length. Given a Markov Chain $\cal M$ and a BPCTL formula Φ, our algorithm checks if Φ is satisfied in $\cal M$. This allows to verify important properties, such as reliability in Discrete Time Hybrid Systems. We present an implementation of our algorithm within a suitable extension of the Mur$\varphi$ verifier. We call FHPMur$\varphi$ (Finite Horizon Probabilistic Mur$\varphi$) such extension of the Mur$\varphi$ verifier. We give experimental results comparing FHPMur$\varphi$ with (a finite horizon subset of) PRISM, a stateoftheart symbolic model checker for Markov Chains. Our experimental results show that FHPMur$\varphi$ can effectively handle verification of BPCTL formulas for systems that are out of reach for PRISM, namely those involving arithmetic operations on the state variables (e.g. hybrid systems).



Giuseppe Della Penna, Benedetto Intrigila, Igor Melatti, Michele Minichino, Ester Ciancamerla, Andrea Parisse, Enrico Tronci, and Marisa Venturini Zilli. "Automatic Verification of a Turbogas Control System with the Mur$\varphi$ Verifier." In Hybrid Systems: Computation and Control, 6th International Workshop, HSCC 2003 Prague, Czech Republic, April 35, 2003, Proceedings, edited by O. Maler and A. Pnueli, 141–155. Lecture Notes in Computer Science 2623. Springer, 2003. ISSN: 3540009132. DOI: 10.1007/354036580X.
Abstract: Automatic analysis of Hybrid Systems poses formidable challenges both from a modeling as well as from a verification point of view. We present a case study on automatic verification of a Turbogas Control System (TCS) using an extended version of the Mur$\varphi$ verifier. TCS is the heart of ICARO, a 2MW Cogenerative Electric Power Plant. For large hybrid systems, as TCS is, the modeling effort accounts for a significant part of the whole verification activity. In order to ease our modeling effort we extended the Mur$\varphi$ verifier by importing the C language long double type (finite precision real numbers) into it. We give experimental results on running our extended Mur$\varphi$ on our TCS model. For example using Mur$\varphi$ we were able to compute an admissible range of values for the variation speed of the user demand of electric power to the turbogas.



Rosario Pugliese, and Enrico Tronci. "Automatic Verification of a Hydroelectric Power Plant." In Third International Symposium of Formal Methods Europe (FME), CoSponsored by IFIP WG 14.3, edited by M.  C. Gaudel and J. Woodcock, 425–444. Lecture Notes in Computer Science 1051. Oxford, UK: Springer, 1996. ISSN: 3540609733. DOI: 10.1007/3540609733_100.
Abstract: We analyze the specification of a hydroelectric power plant by ENEL (the Italian Electric Company). Our goal is to show that for the specification of the plant (its control system in particular) some given properties hold. We were provided with an informal specification of the plant. From such informal specification we wrote a formal specification using the CCS/Meije process algebra formalism. We defined properties using μcalculus. Automatic verification was carried out using model checking. This was done by translating our process algebra definitions (the model) and μcalculus formulas into BDDs. In this paper we present the informal specification of the plant, its formal specification, some of the properties we verified and experimental results.

