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Application of advanced computational methods in drug discovery for targeting RNA
Get PDFThis thesis presents a novel computational approach to RNA-targeted drug discovery, addressing the challenges posed by RNA’s inherent flexibility and the limitations of traditional protein-docking protocols. The first part of the research focuses on two key aspects: druggability prediction and allosteric analysis. We introduce a one-class learning approach using the Import Vector Domain Description (IVDD) algorithm with customized DrugPred descriptors on pockets identified by NanoShaper. This method, validated on a dataset of 100 proteins from the Potential Drug Target Database (PDTD), offers a more nuanced and efficient approach to identifying druggable pockets compared to traditional binary classifications. While the investigation of allostery compares three computational methods – DyNet, DF, and Pocketron – across three pharmaceutical targets: the adenosine A2A receptor, androgen receptor, and EGFR kinase domain. Pocketron consistently demonstrates great performances in identifying known allosteric pockets with high correlation to the orthosteric site. Applying our refined protocols on proteins to the long non-coding RNA MALAT1, we used NanoShaper and Pocketron to identify potential target pockets that could disrupt the triple helix structure through long-range communication. Once the sites were defined we employ molecular dynamics simulations (unbiased and enhanced) to generate a comprehensive conformational ensemble. Having defined the ensembles we generated poses using two pose generation software (AutoDock GPU and rDock), we then evaluated various scoring functions (AutoDock, rDock, Vina, AnnapuRNA, and SPRank) for their ability to predict experimental binding affinities of diminazene-based ligands to MALAT1. Finally, we extend a non-equilibrium binding free energy estimation method to RNA molecules, focusing on the Riboswitch-preQ1 system. Using steered molecular dynamics and the Crooks Fluctuation Theorem, we calculate binding free energies for complexes with both cognate and synthetic ligands. This research contributes to the advancement of RNA-targeted drug discovery by providing novel computational tools and insights into the complex dynamics of RNA-ligand interactions
Safe navigation strategies for quadrotors
Get PDFAutonomous quadcopters are rapidly emerging as a mature technology poised to play a significant role in shaping society in the near future, thanks to their increasing availability and diverse range of applications. From agricultural operations to the transportation of goods and people, these vehicles are set to become an integral part of our daily lives. Given this growing presence, it is crucial to equip these autonomous systems with state-of-the-art algorithms for collision avoidance, which will help prevent damage to people and property, while also ensuring the continued autonomy and operational integrity of the vehicles. The central objective of this thesis is to address this critical challenge. The initial chapters of the thesis provide a comprehensive introduction to the subject matter, including an overview of the relevant literature. We begin by exploring the dynamical model of quadrotors, highlighting its key properties and the challenges these present when designing feasible trajectories for navigating cluttered environments. Following this, we delve into the fundamental concepts of Control Barrier Functions (CBFs) and their application to collision avoidance scenarios. We examine how safety filters can be derived from distance measurements and used to design robust control laws for safe navigation in unknown environments. Finally, driven by the limitations of the sensors commonly employed on autonomous quadrotors—such as monocular and stereo cameras—the concluding section of this work shifts focus towards addressing these constraints. Specifically, we propose an approach based on the CBF framework that accounts for the limited field of view inherent in visual sensors. Additionally, we present a control law, rooted in Control Lyapunov Functions approach, designed to track reference trajectories using feedback based on visual bearings
“Scale-up of cold atmospheric plasma (CAP) source for the production of plasma activated water (PAW)“
Get PDFThis thesis explores the scale-up of cold atmospheric plasma (CAP) sources for producing plasma-activated water (PAW), valued for its unique chemical properties derived from reactive oxygen and nitrogen species (RONS). RONS contributes to PAW’s antimicrobial and oxidative properties, making it valuable in agriculture, healthcare, and environmental remediation. However, efficient large-scale PAW production remains challenging due to declining CAP efficiency with increasing water volumes. The work begins with a systematic review (submitted to Plasma Processes and Polymers) that examines current PAW production methods, analyzing CAP configurations and process variables such as RONS concentration, pH, and energy efficiency. The review highlights various CAP sources, including corona discharge, dielectric barrier discharge (DBD), and plasma jets, examining how parameters like gas type and water composition affect PAW chemistry. Critical challenges for scaling up have also been identified, especially in sustaining high RONS concentrations in larger treatment volumes. Experimental research progresses from a 0.5-liter corona discharge system to a 2-liter DBD setup, increasing the treatment volume fourfold while maintaining RONS concentrations and improving energy efficiency. The research scales PAW production to a 6-liter treatment volume using a multipin corona discharge. This setup addresses challenges such as plasma uniformity and water homogeneity through strategic source placement and mechanical stirring, providing a scalable solution ideal for applications needing large PAW quantities, like agricultural irrigation and soil treatment. Finally, a hybrid CAP source was developed to enhance RONS production further. The optimized design and configuration allowed for greater control over RONS production and improved energy utilization, leading to higher RONS concentrations in treated water than multipin corona. This thesis presents critical insights into parameters for efficient RONS production in large- scale treatments, effectively bridging laboratory results with industrial applications. These findings lay the groundwork for advancing PAW technology, establishing benchmarks for scaling plasma-water treatments across diverse industries
The role of invasive hemodynamic evaluation and pump optimization in the management of patients supported with left ventricular assist devices (LVAD)
Get PDFDespite improved outcomes, LVAD patients still present with frequent rehospitalizations, including those for heart failure (HF). The aim of this study was to investigate the changes in hemodynamic parameters after LVAD implant and the role of hemodynamic optimization obtained by the invasive ramp test (RT) in improving survival and reducing HF admissions. We enrolled patients implanted with centrifugal pumps between 2013 and 2024 who underwent post-implant right catheterization (RHC) during the index hospitalization. Optimal hemodynamics were defined as a right atrial pressure 2.2 l/min/m2. The endpoint was survival free from HF admission according to the hemodynamic profile at 24 months. 63 patients were included in the study. After the implant there was a significant improvement in pulmonary pressure and a reduction in the indices of right ventricular function without changes in central venous pressure. 41% of the patients already had an optimal hemodynamic profile, while 14% achieved it after RT. At 24 months, survival free from HF admission was significantly reduced in patients with non-optimized profiles (81 vs. 58 %, OR 3.2 [1.2-8.2], p = 0.01). This difference was not significant when the effect of the ramp test was not considered (p=0.07). In patients with LVAD, survival free from HF admissions was significantly higher in those with optimized hemodynamics, and RT provided the opportunity to further improve hemodynamic profiles. The non-optimized profile was an independent predictor of mortality and hospitalization for HF
The «constitutional features» of the Cassazione. Origins and transformations
Get PDFQuesta ricerca di dottorato ambisce a studiare la Corte di cassazione e i suoi mutamenti da una prospettiva storico-costituzionale. La prima parte della ricerca è dedicata alle origini del disegno costituzionale e tenta di formulare una proposta di lettura dell’art. 111 Cost. per delineare il «volto costituzionale» del giudice di legittimità, da intendere come insieme di elementi caratterizzanti la Corte di cassazione nell’ottica del Costituente. A partire da tale proposta – che attribuisce una valenza garantista all’art. 111 Cost. – la seconda parte della ricerca analizza le trasformazioni che hanno interessato la Corte di cassazione e il suo «volto costituzionale» nell’ordinamento repubblicano prendendo in considerazione sia la dimensione nazionale che il contesto europeo. Dal primo punto di vista, l’indagine si concentra sull’evoluzione della disciplina processuale del giudizio di legittimità e dei rapporti istituzionali tra Cassazione, Consiglio di Stato, Corte dei conti e Corte costituzionale. Dal secondo punto di vista, la ricerca ricostruisce l’influenza dello sviluppo delle relazioni interordinamentali sul ruolo di sistema della Suprema Corte. La tesi si conclude con un’analisi di alcuni casi di studio in grado di mettere in luce, da un lato, le complementarietà delle dinamiche istituzionali descritte nel corso della trattazione, e dall’altro il bilanciamento concretamente operato dalla Corte tra il suo «volto costituzionale» e la sua anima nomofilattica.This doctoral research focuses on the Italian Corte di Cassazione and its changes from a constitutional-historical perspective. The first part of the research is dedicated to the origins of the constitutional design and tries to make a proposal for the interpretation of Article 111 of the Italian Constitution in order to understand the «constitutional features» of the Court (namely, the set of characteristics of the Cassazione from the Constituent's perspective). Starting from this proposal - which sees Article 111 as a guarantee for citizens - the second part of the thesis analyzes the transformations of the Cassazione and its «constitutional features», taking into consideration both the national and the European context. First, the research focuses on the evolution of the procedural legislation and the institutional relationship between the Cassazione and the Consiglio di Stato, the Corte dei conti and the Constitutional court. Second, the research focuses on the influence of the European integration process on the systemic role of the Cassazione. The thesis ends with case-study that shows, on the one hand, the complementarities of the institutional dynamics described in the previous chapters, and on the other, the balance between the Cassazione’s «constitutional features» and its nomofilachia
Use of in vitro alternative methods in the study of emerging contaminants for identifying mechanisms of action in non-genotoxic carcinogenesis
Get PDFChemical carcinogenesis driven by non-genotoxic compounds is a challenging and dynamic research area. Unlike genotoxic carcinogens, non-genotoxic agents such as di-(2-ethylhexyl) phthalate (DEHP) and perfluorooctane sulfonic acid (PFOS) induce cancer via indirect mechanisms, often involving receptor-mediated pathways. This thesis investigated the carcinogenic potential of DEHP and PFOS in the BALB/c 3T3 A31-1-1 cell model using the Cell Transformation Assay (CTA) and explored their molecular mechanisms with a focus on PPARα activation, a pathway implicated in rodent tumorigenesis. DEHP was assessed through CTA coupled with transcriptomics to identify post-exposure molecular alterations, offering insights into its mechanism of action. The results showed that DEHP did not induce cellular transformation in vitro. Comparative analysis with other CTA studies highlighted variations in model responses, highlighting the critical importance of characterizing compound metabolism. PFOS, which is known for its receptor-mediated effects, was evaluated by co-treatment with GW6471, a PPARα antagonist. Although PFOS induced cellular transformation, the involvement of PPARα alone was insufficient to explain its carcinogenicity in the BALB c/ 3T3 A31-1-1 cell model, suggesting the participation of alternative pathways. Key findings from this study demonstrated that although both compounds can activate PPARα, they exhibit different mechanisms of action. This study underscores the complexity of non-genotoxic carcinogenesis, in which receptor-mediated events, metabolic alterations, and disruptions in signaling pathways interact to promote tumorigenesis. The integration of CTA with additional mechanistic approaches, such as transcriptomics for DEHP and the use of a PPARα inhibitor for PFOS, has allowed for deeper investigation into the mechanisms of action underlying the cellular effects observed. These findings promote the enhancement of CTA within Integrated Approaches to Testing and Assessment (IATA) for non-genotoxic compounds, emphasizing the need for refined in vitro models to better replicate human responses and improve chemical risk assessment for public health
Hidden in plain sight: detecting misogyny beneath ambiguities and implicit bias in language
Get PDFThis thesis explores NLP methods for detecting misogyny in social media, ranging from explicit instances to implicit and ambiguous expressions that vary across languages and platforms. With a focus on Italian and English, the research investigates monolingual, cross-lingual, and multimodal approaches, leveraging transformer-based models and large language models (LLMs). It critically examines the limitations of these models in misogyny detection, particularly in handling unintended biases related to identity terms, the ambiguity of pejorative language, and the implicit nature of harmful discourse. A key contribution of this work is the conceptualization of pejorative epithet disambiguation as a necessary step for misogyny detection, framed as a word sense disambiguation task. To support this, the thesis introduces PejorativITy, a newly developed corpus for pejorative epithets in Italian. Beyond explicit misogyny, this research delves into the complexities of implicit misogyny detection and explanation, investigating how LLMs can help uncover the underlying assumptions embedded in misogynistic language. To facilitate these experiments, the thesis introduces ImplicIT-Mis, the first dataset specifically designed for implicit misogyny in Italian. The study evaluates LLMs’ ability to recognize and reconstruct implied meanings in misogynistic statements, which often require nuanced comprehension of social cues, stereotypes, irony, and backhanded compliments—elements that challenge traditional classification methods reliant on explicit hate speech markers. A unique aspect of this research is the application of argumentation theory, which helps decompose inferential processes behind misogynistic language. By incorporating reasoning-based detection tasks, the experiments reveal both the strengths and limitations of LLMs in capturing hidden social dynamics. The findings emphasize the potential of NLP models in identifying misogyny but highlight ongoing challenges in developing context-aware, multilingual models capable of adapting to the ever-evolving landscape of online discourse
p-BE index: modeling the structural relationship between the physical built environment and cancer outcomes within the biopsychosocial framework.
No full textCancer patients face complex challenges, not only the physical side effects of treatments but also because of the psychosocial consequences. These are further exacerbated by limited funding, inadequate infrastructure, and other difficulties in cancer care. Research has identified two key environments during cancer care: the residence and the oncology infrastructure (OI). While studies focus on the role of residence in accessibility and treatment adherence, less attention has been given to the OI, despite it being transversal for all patients within the same healthcare system. This study adopts a user-centered approach to explore the impact of the OI on physical, psychological, and social health. The p-BE index was developed and tested as a tool to evaluate both the OI and the patient’s residential area. The p-BE index has two components: the architectural p-BE index, which measures infrastructural and organizational characteristics of the OI, and the urban p-BE index, which evaluates the surrounding residential area. These scores are analyzed in relation to patients’ wellbeing and perceptions, designed to be integrated in the future with other databases, linking infrastructural and behavioral data. The findings showed no correlations between the urban p-BE index and wellbeing scores, suggesting that wellbeing may be more influenced by the characteristics of the residence or other factors. In contrast, the architectural p-BE index showed correlations in four of the six aspects examined, highlighting how inadequate infrastructure can negatively impact physical, psychological, and social wellbeing. This represents an unnecessary risk for patients and demonstrates the value of the digital twin as a valuable data source for health. The p-BE index helps evaluate patient experience in health environments and OI performance, with the goal of identifying avoidable risks and transforming infrastructure into an active tool for patient-centered healthcare.I pazienti oncologici e il cancer care affrontano sfide complesse, non solo a causa degli effetti collaterali fisici dei trattamenti, ma anche per le conseguenze psicosociali. Queste problematiche sono aggravate da finanziamenti limitati, infrastrutture inadeguate e altre difficoltà. La ricerca ha identificato due ambienti chiave durante il periodo del cancer care: la residenza e l’infrastruttura oncologica (OI). Mentre numerosi studi hanno analizzato il ruolo della residenza nell’accessibilità alle cure e nell’aderenza al trattamento, si è prestata scarsa attenzione all’OI, nonostante la sua rilevanza universale per tutti i pazienti all’interno dello stesso sistema sanitario. Questo studio adotta un approccio incentrato sull’utente per esplorare l’impatto dell’OI sulla salute fisica, psicologica e sociale. È stato sviluppato e testato il p-BE index, uno strumento progettato per valutare sia l’OI che l’area residenziale del paziente. Il p-BE index comprende due componenti: l’indice architettonico p-BE, che misura le caratteristiche infrastrutturali e organizzative dell’OI, e l’indice urbano p-BE, che valuta l’area residenziale circostante. Questi punteggi sono analizzati in relazione al benessere e alle percezioni dei pazienti, e sono stati progettati per essere integrati in futuro con altri database, collegando dati infrastrutturali e comportamentali. I risultati non hanno mostrato correlazioni tra l’indice urbano p-BE e i punteggi di benessere, suggerendo che quest’ultimo potrebbe essere influenzato maggiormente dalle caratteristiche della residenza o da altri fattori non misurati. Al contrario, l’indice architettonico p-BE ha mostrato correlazioni in quattro dei sei aspetti esaminati, evidenziando come infrastrutture inadeguate possano avere un impatto negativo sul benessere fisico, psicologico e sociale, dimostrando così il valore del digital twin come fonte di dati preziosa per la salute. Come strumento per valutare l’esperienza del paziente e l’efficienza dell’OI, il p-BE index supporta il cancer care, individuando rischi evitabili e trasformando l’infrastruttura in uno strumento attivo di assistenza sanitaria centrata sul paziente
The governance of digital transformation of public administration: the role of public bodies and civil society's watchdogs in Portugal and Italy
Get PDFThis dissertation examines the governance of digital transformation of public administrations in Portugal and Italy. Digital transformation is often framed as a top-down, technology-driven process. The dissertation offers an under-explored perspective, adopting a practice-based approach. Specifically, it examines two key phenomena: the orchestration and monitoring of digital initiatives. Orchestration refers to the coordination of resources, processes, and actors – often through the use of digital technologies – to achieve cohesive and effective digital transformation outcomes. Monitoring digital transformation encompasses the oversight activities carried out by civil society actors to scrutinize digital and technological issues that are perceived as potentially problematic within increasingly data-driven societies. Through a comparative case study, the research draws on qualitative data from public bodies and civil society organizations in both countries, offering a grounded analysis of how digital transformation unfolds in practice in two southern European countries. The findings reveal that while supranational influences, such as the EU’s policies, drive some convergence in practices, local political and institutional contexts lead to differences between the two countries. Public bodies, especially in Portugal, tend to centralize governance, whereas Italy’s fragmented approach presents more challenges. Civil society’s monitoring efforts, though impactful, face some resistance. Furthermore, the study highlights a concerning lack of meaningful interaction between public institutions and civil society watchdogs, potentially leading to a one-sided governance model. This raises important questions about the need for more collaborative, transparent, and socially responsive approaches to digital transformation. Overall, this dissertation contributes to the literature on digital transformation and governance by showing how practice theories can provide a richer and more nuanced understanding of the processes and actors involved
Unraveling the role of extracellular vesicles in myeloproliferative neoplasms
No full textMyeloproliferative neoplasms (MPNs) are rare hematological disorders characterized by excessive blood cell production and a tendency to progress to acute myeloid leukemia. Despite advances in understanding the genetic basis of MPNs, many aspects remain unexplored about the disease complex interplay between neoplastic cells and their surroundings. Advancements in these areas are crucial for developing improved treatments and identifying biomarkers for MPN. Addressing factors other than genetic alterations may play a role in the origin, evolution and progression of the disease and could, therefore, be the target of new therapies as well. During my PhD program, I had the privilege of working not only at the Institute of Hematology “L. e A. Seràgnoli” of the University of Bologna, but also at two companies. These experiences allowed me to gain a deeper understanding of the interplay between academia and industry, enriching my research and equipping me with skills to navigate both scientific and entrepreneurial environments. Additionally, I gained extensive experience in cross-disciplinary collaboration by working with research groups from diverse faculties, including the Departments of Biochemistry and Molecular Biology as well as Chemistry. This exposure broadened my scientific perspective and strengthened my ability to work effectively in diverse, collaborative environments. In conclusion, I hope that my PhD thesis has made a meaningful contribution to the better understanding of MPN diseases by providing insights that may support the development of diagnostic and therapeutic biomarkers. Improving EV isolation using HF5 represents a step toward more refined techniques, which, when combined with omics data, could open new avenues for exploring the biology of MPNs. I am hopeful that these advancements will aid in facilitating translational research and ultimately contribute to the development of more targeted and effective therapeutic strategies for MPN patients