Closed-loop investigation of the dynamical properties of cardiomyocyte electrophysiology by means of Dynamic clamp and Mathematical modelling

The research field of my PhD concerns mathematical modeling and numerical simulation, applied to the cardiac electrophysiology analysis at a single cell level. This is possible thanks to the development of mathematical descriptions of single cellular components, ionic channels, pumps, exchangers and subcellular compartments. Due to the difficulties of vivo experiments on human cells, most of the measurements are acquired in vitro using animal models (e.g. guinea pig, dog, rabbit). Moreover, to study the cardiac action potential and all its features, it is necessary to acquire more specific knowledge about single ionic currents that contribute to the cardiac activity. Electrophysiological models of the heart have become very accurate in recent years giving rise to extremely complicated systems of differential equations. Although describing the behavior of cardiac cells quite well, the models are computationally demanding for numerical simulations and are very difficult to analyze from a mathematical (dynamical-systems) viewpoint. Simplified mathematical models that capture the underlying dynamics to a certain extent are therefore frequently used. The results presented in this thesis have confirmed that a close integration of computational modeling and experimental recordings in real myocytes, as performed by dynamic clamp, is a useful tool in enhancing our understanding of various components of normal cardiac electrophysiology, but also arrhythmogenic mechanisms in a pathological condition, especially when fully integrated with experimental data

Mechanical properties of the most common European woods: a literature review

Wood is an orthotropic material used since ancient time. A literature research about the mechanical properties of density, fracture toughness, modulus of elasticity, and Poisson’s ratio has been done to have a broader view on the subject. The publications relating to the topic were found through the two search engines Scopus and Google Scholar that have yielded several papers, including articles and book sections. In general, there is no standardization on the method of analysis carried out on wood, underlining the great difficulty in studying this complex material. The parameter of density has a great variability and needs a deeper investigation; fracture toughness is not always available in literature, not even in the different directions of the wood sample. Interesting is the modulus of elasticity, which provides a correlation with density, especially in longitudinal section but, again, it needs to be studied in detail. The parameter of Poisson’s ratio is provided as single values in three different directions, but mainly for softwood. All the parameters require a more in-depth study for both softwood and hardwood. Furthermore, the type of analysis, whether experimental or modelling, needs to be standardized to have more comparable results

Prevalence of temporomandibular disorders in adult obstructive sleep apnoea patients: A cross-sectional controlled study

Background: Obstructive sleep apnoea (OSA) is characterised by partial or complete obstruction of the upper airways during sleep and it has been associated with temporomandibular disorders (TMDs) on the basis of several pathophysiological hypotheses. Objectives:To assess the prevalence of TMDs in a population of patients affected by OSA compared to a control group of subjects not affected by OSA. MethodsA cross-sectional controlled study was conducted on a group subjects studied by polygraphy (PG) at the snoring section of the ENT department, Sant'Orsola-Malpighi Hospital - University of Bologna. Patients who received a diagnosis of OSA were included in the study group and subjects with a negative PG diagnosis for Sleep Disordered Breathing and PG respiratory pattern that did not suggest the occurrence of sleep disorders were enrolled in the control group. Both the subjects included in the study group and the control group underwent an examination following the Diagnostic Criteria for Temporomandibular Disorders Axis I and II. Results: Forty-three OSA patients (29 M, 16 F, mean age 52.26 +/- 11.40) and 43 healthy controls (25 M, 18 F, mean age 49.95 +/- 7.59) were included in the study. No significant differences were found between groups in demographic data. TMD prevalence and Axis II results did not differ between groups. Conclusions: This paper does not highlight a higher prevalence of TMDs in adults with OSA compared to healthy controls. Further high-quality studies are needed to confirm the results and to give possible pathophysiological explanations, providing reliable evidence

Sensitivity of the Human Ventricular BPS2020 Action Potential Model to the In Silico Mechanisms of Ischemia.

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A dynamic clamping approach using in silico IK1 current for discrimination of chamber-specific hiPSC-derived cardiomyocytes

: Human induced pluripotent stem cell (hiPSC)-derived cardiomyocytes (CM) constitute a mixed population of ventricular-, atrial-, nodal-like cells, limiting the reliability for studying chamber-specific disease mechanisms. Previous studies characterised CM phenotype based on action potential (AP) morphology, but the classification criteria were still undefined. Our aim was to use in silico models to develop an automated approach for discriminating the electrophysiological differences between hiPSC-CM. We propose the dynamic clamp (DC) technique with the injection of a specific IK1 current as a tool for deriving nine electrical biomarkers and blindly classifying differentiated CM. An unsupervised learning algorithm was applied to discriminate CM phenotypes and principal component analysis was used to visualise cell clustering. Pharmacological validation was performed by specific ion channel blocker and receptor agonist. The proposed approach improves the translational relevance of the hiPSC-CM model for studying mechanisms underlying inherited or acquired atrial arrhythmias in human CM, and for screening anti-arrhythmic agents

Proteomic profiling of extracellular vesicles in synovial fluid and plasma from Oligoarticular Juvenile Idiopathic Arthritis patients reveals novel immunopathogenic biomarkers

IntroductionNew early low-invasive biomarkers are demanded for the management of Oligoarticular Juvenile Idiopathic Arthritis (OJIA), the most common chronic pediatric rheumatic disease in Western countries and a leading cause of disability. A deeper understanding of the molecular basis of OJIA pathophysiology is essential for identifying new biomarkers for earlier disease diagnosis and patient stratification and to guide targeted therapeutic intervention. Proteomic profiling of extracellular vesicles (EVs) released in biological fluids has recently emerged as a minimally invasive approach to elucidate adult arthritis pathogenic mechanisms and identify new biomarkers. However, EV-prot expression and potential as biomarkers in OJIA have not been explored. This study represents the first detailed longitudinal characterization of the EV-proteome in OJIA patients.MethodsFourty-five OJIA patients were recruited at disease onset and followed up for 24 months, and protein expression profiling was carried out by liquid chromatography-tandem mass spectrometry in EVs isolated from plasma (PL) and synovial fluid (SF) samples.ResultsWe first compared the EV-proteome of SF vs paired PL and identified a panel of EV-prots whose expression was significantly deregulated in SF. Interaction network and GO enrichment analyses performed on deregulated EV-prots through STRING database and ShinyGO webserver revealed enrichment in processes related to cartilage/bone metabolism and inflammation, suggesting their role in OJIA pathogenesis and potential value as early molecular indicators of OJIA development. Comparative analysis of the EV-proteome in PL and SF from OJIA patients vs PL from age/gender-matched control children was then carried out. We detected altered expression of a panel of EV-prots able to differentiate new-onset OJIA patients from control children, potentially representing a disease-associated signature measurable at both the systemic and local levels with diagnostic potential. Deregulated EV-prots were significantly associated with biological processes related to innate immunity, antigen processing and presentation, and cytoskeleton organization. Finally, we ran WGCNA on the SF- and PL-derived EV-prot datasets and identified a few EV-prot modules associated with different clinical parameters stratifying OJIA patients in distinct subgroups.DiscussionThese data provide novel mechanistic insights into OJIA pathophysiology and an important contribution in the search of new candidate molecular biomarkers for the disease