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Revving up future mobility: hybridization, alternative fuels and the renaissance of the 2-stroke engine cycle
No full textThis PhD thesis explores advancements in internal combustion engines (ICEs) through hybridization, alternative fuels, and two-stroke (2S) engine design updates to reduce emissions and improve efficiency. Key research areas include hybrid powertrains for motorcycles and aircraft, ethanol-based biofuels for small to medium-duty engines, and hydrogen deployment in two- and four-stroke engines.
The study examines 2S engine architectures, comparing scavenging methodologies in opposed-piston uniflow, conventional loop, and reverse loop designs. It also investigates hybrid-electric applications in motorcycles and ultralight aircraft, assessing efficiency gains. Additionally, ethanol-based biofuels are tested in opposed-piston and 4-stroke engines with minimal modifications.
Results show that optimized 2S engines running on hydrogen or biofuels offer high efficiency and low emissions. Hydrogen-fueled opposed-piston engines demonstrate near-zero NOx emissions and high thermal efficiency, making them suitable for power generation and high-power-density applications.
This research highlights ICEs' continued relevance in a sustainable energy landscape, advocating for a balanced approach integrating ICE advancements, sustainable fuels, electrification, and fuel cells. Through computational fluid dynamics (CFD) simulations and experimental validation, it contributes to developing cleaner, high-performance ICE technologies
"Icarus Fate": Alessandro Manzoni and the modern concept of the tragic
No full textIl presente studio affronta uno dei punti più complessi e, forse, meno approfonditi della critica manzoniana: il problema del tragico, nelle tragedie e nei romanzi, nello specifico in Fermo e Lucia e nei Promessi sposi. Partendo dalla convinzione che la teoria del tragico permanga nella narrativa manzoniana e adottando le idee sul tragico moderno sistematizzate dallo studioso Peter Szondi, si propone di far emergere ciò che Manzoni ha trattenuto del concetto di tragico nella sua prima prova romanzesca, Fermo e Lucia — redatta nel 1821, parallelamente alla stesura dell’Adelchi — e successivamente nella Quarantana. Tale indagine si colloca all’interno del percorso manzoniano in cui l’autore, dopo essersi a lungo dedicato alla formulazione di un nuovo sistema teorico, sperimenta l’applicazione di esso nelle due tragedie, sebbene attraverso strategie differenti. Nello specifico, si renderà conto, tenute presenti puntuali premesse teoriche di ordine estetico-filosofico ed ermeneutico, di come nella narrativa manzoniana sia presente il concetto moderno di tragico.This study addresses one of the most complex and, perhaps, least explored aspects of Manzonian criticism: the problem of the tragic in both his tragedies and novels, specifically in Fermo e Lucia and I Promessi Sposi. Starting from the conviction that the theory of the tragic persists in Manzoni’s narrative and adopting the ideas on modern tragedy systematized by scholar Peter Szondi, this research aims to bring to light what Manzoni retained of the concept of the tragic in his first novelistic attempt, Fermo e Lucia—written in 1821, concurrently with the composition of Adelchi—and later in the Quarantana. This inquiry is situated within Manzoni’s intellectual trajectory, in which the author, after long engaging in the formulation of a new theoretical system, experiments with its application in his two tragedies, albeit through different strategies. More specifically, by taking into account precise theoretical premises of an aesthetic-philosophical and hermeneutic nature, this study will demonstrate how the modern concept of the tragic is present in Manzoni’s narrative
Innovative materials for sustainable road pavements: recycling and performance from subgrade to surface layer
No full textThe road construction sector is implementing major developments in line with sustainability strategies and policies to address environmental, economic and social impacts across the life cycle of road pavements. It is vital that strategies for the reuse of recycled materials are developed and promoted, with particular attention paid to mixture design and material performance to reduce construction and maintenance interventions. The goal of this research is to provide a comprehensive analysis of the feasibility and applicability of high percentages of recycled materials in transport infrastructure, with a particular focus on high-performance road pavements. Multiple recycled materials have been characterised and designed in laboratory to develop solutions for application across road structure layers in order to evaluate the potential for reuse in sustainable, high-quality and durable pavements. The analysis investigates the valorisation of dredged sediments as a new resource for road subgrade and the design of asphalt concrete mixtures containing Reclaimed Asphalt Pavement (RAP) and steel slag for wearing courses with improved mechanical performance. The design of durable pavements requires the evaluation of the pavement response at critical points of investigation to assess the structural distresses and minimise the damage to the pavement over its service life. The implementation of advanced software for modelling and designing road pavement infrastructure simplifies the process of developing solutions that are safe, efficient, and environmentally sustainable. The performance prediction of infrastructure solutions with high percentages of recycled materials in the different constituent layers through the implementation of road design software based on the continuum finite-layer approach is presented. The materials analysed in this research exhibited mechanical responses comparable to those observed in traditional mixtures. The investigation of solutions comprising recycled materials that simultaneously exhibit superior mechanical performance represents a fundamental initiative towards sustainability
Myoclonic epilepsy with ragged-red fibers: advancing personalized medicine through iPSC manipulation and neural modelling
No full textMyoclonic Epilepsy with Ragged-Red Fibers (MERRF) is a rare genetic condition mostly associated with the m.8344A>G substitution within the mitochondrial MT-TK gene, which codes for mt-tRNALys. The biochemical dysfunctions encompass premature mitochondrial protein termination, aberrant OXPHOS subunit polypeptides and bioenergetic failure, ensuing in increased oxidative stress, inflammation and progressive neurodegeneration. Nevertheless, the overarching pathogenic mechanisms of the disease remain elusive. This study aimed to generate MERRF induced pluripotent stem cells (iPSCs) from patient-derived somatic cells, expanding on the fine-tuning of alternative approaches to shift heteroplasmy artificially. MERRF iPSCs were leveraged for neural differentiation into neural progenitors and cortical organoids, as well as for the repurposing of rapamycin as a therapeutic strategy. However, the reprogramming efficiency to high-heteroplasmy iPSCs was negligible. Low-heteroplasmy cortical organoids were generated, but only revealed a decline in the expression of common NPC and synaptic markers, as well as morphological aberrations associated with an astrocytic depletion. Inducing a genetic bottleneck in iPSCs with ethidium bromide allowed to obtain multiple clones with variable m.8344A>G load proportions. Conversely, mitochondrial transfer from high-heteroplasmy cybrid donor cells to isogenic wild-type or intermediate-heteroplasmy iPSC recipients proved inefficient. NPCs generated from intermediate and high-heteroplasmy MERRF iPSCs showed an increased mitochondrial DNA content, while oxygen consumption revealed an increment in the steady-state levels of basal respiration in high-heteroplasmy NPCs. Rapamycin treatment led to an increase in mtDNA copy number associated with improved respiration only for the intermediate MERRF NPC cell line. MERRF cortical organoids were established from high-heteroplasmy iPSCs to optimize rapamycin treatment, which indicated that late-stage incubation is recommended to avoid developmental inhibition. In conclusion, this study presented an efficient method to circumvent the challenges associated with high-heteroplasmy iPSC reprogramming and introduced 3D cortical organoids for MERRF, which will be used for further investigations into the potential therapeutic effects of rapamycin
L'eredità musicale antica nel De modis musicis antiquorum di Girolamo Mei. Con un'edizione e una traduzione francese del testo
No full textPhilologue et humaniste florentin du XVIe siècle, Girolamo Mei (1519-1594) joua un rôle majeur dans la redécouverte des théories musicales antiques à la Renaissance. Tandis que les scriptores musici commençaient à sortir de l’ombre depuis quelques décennies en Italie, les quatre livres du De modis musicis antiquorum offrent une première étude approfondie du système musical grec. Dans ce traité, Mei est le premier théoricien moderne à dissocier nettement les « modes » grecs (tonoi) des octaves modales de son temps. Parvenu à la conclusion que la musique antique, par sa nature monodique, aurait été capable de susciter des effets merveilleux sur l’âme humaine, l’auteur se livre aussi à un ardent plaidoyer à l’encontre de la polyphonie de son temps. Ses idées, diffusées à Florence par l’intermédiaire de Vincenzo Galilei, eurent une influence non négligeable sur l’humanisme musical. Le traité de Mei resta manuscrit plus de quatre siècles. Une seule édition en existe à ce jour, réalisée en 1991 par Eisuke Tsugami. Cette édition n’est accompagnée d’aucune traduction en langue moderne et d’aucun commentaire spécifique. L’objectif de cette recherche doctorale fut de proposer une première étude systématique de ce texte et de préciser son importance dans la transmission d’un héritage musical antique à la Renaissance. Cette étude permet aussi de mettre en lumière de nouveaux éléments sur le parcours de vie de Girolamo Mei, sur ses méthodes de travail et la transmission de son traité dans les années qui ont suivi sa mort. La seconde partie de la thèse propose une nouvelle édition critique du texte latin, accompagnée d’une première traduction en langue française.Il filologo e umanista fiorentino Girolamo Mei (1519-1594) ha svolto un ruolo fondamentale nella riscoperta delle teorie musicali antiche durante il Rinascimento. Mentre gli scriptores musici emergevano dall’oscurità in Italia già da alcuni decenni, i quattro libri del De modis musicis antiquorum offrono il primo studio approfondito del sistema musicale greco. In questo trattato, Mei fu il primo teorico moderno a distinguere chiaramente i “modi” greci (tonoi) e le ottave modali del suo tempo. Convinto che la natura monodica della musica antica fosse in grado di produrre effetti meravigliosi sull’animo umano, fece anche un ardente appello contro la polifonia del suo tempo. Le sue idee, diffuse a Firenze attraverso Vincenzo Galilei, ebbero un’influenza significativa sull’umanesimo musicale. Il trattato di Mei rimase manoscritto per più di quattro secoli. Ad oggi esiste una sola edizione, realizzata nel 1991 da Eisuke Tsugami. Questa edizione non è accompagnata da una traduzione moderna o da un commento specifico. L’obiettivo di questa ricerca di dottorato è stato quello di offrire il primo studio sistematico di questo testo e di chiarire la sua importanza nella trasmissione di un antico patrimonio musicale al Rinascimento. Lo studio getta inoltre nuova luce sulla vita di Girolamo Mei, sui suoi metodi di lavoro e sulla trasmissione del suo trattato negli anni successivi alla sua morte. La seconda parte della tesi propone una nuova edizione critica del testo latino, accompagnata da una prima traduzione in francese.Sixteenth-century Florentine philologist and humanist Girolamo Mei (1519-1594) played a major role in the rediscovery of ancient musical theories during the Renaissance. While scriptores musici had been emerging from obscurity in Italy for a few decades, the four books of De modis musicis antiquorum offer the first in-depth study of the Greek musical system. In this treatise, Mei was the first modern theorist to make a clear distinction between the Greek ‘modes’ (tonoi) and the modal octaves of his time. He concluded that the monodic nature of ancient music was capable of producing marvellous effects on the human soul, and he also made an ardent plea against the polyphony of his time. His ideas, disseminated in Florence through Vincenzo Galilei, had a significant influence on musical humanism. Mei’s treatise remained in manuscript for more than four centuries. Only one edition exists to date, produced in 1991 by Eisuke Tsugami. This edition is not accompanied by a modern translation or any specific commentary. The aim of this doctoral research was to offer the first systematic study of this text and to clarify its importance in the transmission of an ancient musical legacy to the Renaissance. The study also sheds new light on Girolamo Mei’s life, his working methods and the transmission of his treatise in the years following his death. The second part of the thesis offers a new critical edition of the Latin text, accompanied by a first translation into French
Numerical and experimental investigations of single and multiphase flows in microchannels
No full textIn this thesis, different aspects of microfluidics are deeply studied, employing a wide array of methods including Computational Fluid Dynamics modelling, machine learning algorithms, image processing, Particle Image Velocimetry (PIV), and Particle Tracking Velocimetry (PTV). This approach allows for an extensive analysis of some phenomena in microfluidics, highlighting the field’s interdisciplinary and innovative nature. The first part of this thesis examines microdrop formation within microjunctions, addressing gaps in this long-studied field. An automatic algorithm was developed to analyze droplet formation, complemented by PIV, providing a robust tool for validating numerical simulations. Validation focused on droplet sizes under various flow conditions, interface dynamics during breakup, and velocity fields within droplets. The validated simulations were further used to develop new models that describe the dimensions of the droplets. Moreover, an optimization approach was introduced to provide operational parameters for achieving droplets of the desired sizes. The second part of this thesis focused on thermal phenomena within microchannels. Typically, buoyancy effects are often neglected in microfluidic applications due to the small dimension of the channels. However, it was demonstrated that mixed convection can occur even under relatively low thermal gradients. To characterize this phenomenon, an approach combining numerical and experimental methods was used. Specifically, the flow was analyzed with PIV and PTV techniquesl. Moreover, numerical simulations were performed to study the temperature distribution and mass transfer within these devices. The thesis concludes with a numerical analysis and the development of a simplified model for simulating the hybrid primary heat exchanger in a nuclear reactor. This model achieves comparable results to the full model while reducing computation times, supporting experimental testing to characterize the component. The methodologies presented provide a multi-scale framework for designing, modeling, and validating innovative microchannel heat exchangers in forced and mixed convection regimes
Analysis and validation of gene polymorphisms in osteosarcoma
No full textOsteosarcoma (OS) is an aggressive bone tumor for which the cure rate has not significantly improved in the last 30 years. OS is treated with neoadjuvant chemotherapy regimens, whose effectiveness can be opposed by drug resistance mechanisms that decrease treatment response and cure probability. Moreover, the problem of treatment-related adverse events has to be seriously taken into consideration because it can negatively affect patients' quality of life. It is therefore necessary to identify novel biomarkers, which can distinguish patients who are at risk of developing drug resistance or collateral toxicity due to chemotherapy. In the past years, candidate gene polymorphisms have been indicated to be involved in response to chemotherapy and/or susceptibility to treatment-related toxicity in OS patients, but this information needs further validation. The aim of this PhD project is to validate the clinical impact of candidate gene polymorphisms, which have been highlighted in previous studies and to better define their possible predictive value. Candidate gene polymorphisms, therefore, have been analyzed in a panel of human OS cell lines, either sensitive or resistant to conventional chemotherapy drugs, to confirm their role in the development of drug resistance. Moreover, the same polymorphisms have been evaluated in OS clinical samples to validate their predictiveness for the OS development and their prognostic value. Finally, to study the involvement of these polymorphisms in the development of collateral toxicity due to the use of chemotherapy, a human kidney model has been developed to allow future research aimed to better clarify how single nucleotide polymorphisms may contribute to the development of toxicity in this organ. The results achieved in this project are essential to identify single nucleotide polymorphisms that are important in the development of OS but most of all in treatment unresponsiveness, which may be used to draw more personalized treatments
Sustainable production of nutraceuticals and bioactives from food waste: application to cashew nutshell liquid
No full textThe global generation of millions of tonnes of biowaste highlights the need for sustainable valorisation strategies that tackle environmental and health challenges. In alignment with the United Nations' Sustainable Development Goals (SDGs), there is growing interest in environmentally friendly solutions within the pharmaceutical and nutraceutical sectors. Green chemistry promotes the use of renewable, less harmful raw materials, but the integration of biomass-derived compounds in drug development remains an open challenge. Agro-industrial by-products like food waste, offer a promising source of bioactive compounds for pharmaceutical applications. Cashew nutshell liquid (CNSL), an abundant by-product of the cashew industry, is rich in phenolic lipids, characterised by a unique pentadactyl alkyl side chain. Due to its chemical properties, CNSL holds great promise for sustainable drug development. This thesis explores CNSL’s potential through the lens of green chemistry and the One Health approach, which emphasizes the interconnection between human, animal, and environmental health. The aim is to develop sustainable pharmaceuticals, nutraceuticals, and cosmeceuticals while contributing to the circular economy. Based on these considerations, CNSL has been investigated for its potential applications in four complementary projects. Chapter 2 presents novel CNSL-derived mitochondria-targeting phosphonium and ammonium salts with potent antiparasitic activity against Trypanosoma and Leishmania species. Chapter 3 investigates biocatalysis as a green method for CNSL functionalisation to create pharmaceutical precursors. Chapter 4 evaluates CNSL’s application in nutraceuticals and cosmeceuticals, particularly in liposomal formulations aimed at treating skin disorders. Chapter 5 explores CNSL-derived CRBN binder-linker constructs as E3 ligase ligands for the development of Proteolysis Targeting Chimeras (PROTACs), a cutting-edge drug discovery platform. In summary, this work demonstrates CNSL’s potential as a renewable, sustainable resource for therapeutic innovation. The findings advance the integration of waste valorisation into pharmaceutical research, supporting the global shift toward green chemistry and sustainable development in both human and veterinary medicine
Inestigation oncellular elements involved in Parvovirus B19 infection
No full textHuman Parvovirus B19 (B19V) is a ssDNA virus classified within the Erythrovirus genus of the Parvoviridae family. B19V exhibits a selective tropism for erythroid progenitor cells (EPCs) within the bone marrow.
The cellular susceptibility and permissiveness to B19V may be explained by a complex combination of several factors. Regarding the expression of specific co-receptors on the surface of the target cells, the VP1u binding coreceptor (VP1u-coR) has been identified as a molecule involved in the B19V entry step.
The precise impact of B19V on EPCs remains to be fully elucidated. Therefore, the objective of this study is to gain a deeper understanding of the interactions between B19V and EPCs.
The phenotypic characterisation of the cells using flow cytometric analysis for erythroid surface markers and B19V coreceptor substantiates the hypothesis that the efficacy of viral replication is critically linked to the cell differentiation state. Furthermore, an enrichment of the VP1u-coR-expressing cell fraction was conducted through FACS to assess the potential role of VP1u-coR during the infectious process. The results suggest that this interaction may play a role in the later stages of infection, leading to a productive replicative cycle.
mRNAseq analysis enabled the characterisation of B19V-induced effects on both the host and viral expression profiles, thereby enhancing our understanding of the pathogenic potential of this virus.
The research conducted in Zahra Kadri's laboratory focused on the role of SAMHD1 as host restriction/permissiveness factors against B19V in a bank of UT7/EPO subclones with increasing graded permissiveness towards B19V. These cells were engineered using the CRISPR/Cas9 technique to knockout the SAMHD1 gene. The results obtained do not allow us to conclude whether SAMHD1 acts as a restriction or permissive factor during B19V infection. It would be beneficial to elucidate the potential correlation between SAMHD1 and B19V, which appears to be an indirect one
Drug-induced impulse control disorders: integrating pharmacovigilance findings into the cumulative evidence synthesis process.
No full textImpulse control disorders (ICoDs), including pathological gambling, compulsive shopping, and hypersexuality, significantly impair quality of life. Traditionally regarded as always idiopathic, ICoDs have also been recognized as adverse drug reactions (ADRs) over the past 25 years, with individual case safety reports–ICSRs providing unique insights.
This PhD project aims to expand our understanding of drug-induced ICoDs by challenging the notion that ICSRs and disproportionality analysis (DPA) are only for preliminary signal detection. The simplicity of DPA has led to misuse and misinterpretation, leading several pharmacovigilance experts to advocate for its preclusion from the scientific literature. Nonetheless, integrative approaches to DPA show it can offer more profound insights. This project proposes a methodology that enhances the utility of ICSRs and DPA by incorporating established knowledge and complementary tools.
The project begins with phenotyping ICoDs in ICSRs, validating an operational definition through a scoping review and DPA and analysing free-text narratives to identify irrelevant reports. I use this enhanced understanding of ICoDs phenotype to integrate disproportionality analysis with Bradford Hill’s criteria, organizing intrinsic and extrinsic evidence for a class effect by third-generation antipsychotics.
In the absence of a comprehensive mechanistic explanation for drug-induced ICoDs, DPA combined with pharmacometrics suggested a potential pathogenetic mechanism involving 5-HT1a receptor agonism. Additionally, network analysis combined with an event-event disproportionality analysis characterized ICoDs as a dynamic syndrome, identifying behavior-specific sub-syndromes and potential exacerbating events, and pointing to possible therapeutic targets.
Beyond advancing knowledge on drug-induced ICoDs, this PhD work contributes to methodological advances in DPA and ICSRs, advocating for a Bayesian epistemological framework in pharmacovigilance. This framework integrates intrinsic and extrinsic evidence, empowering pharmacovigilance to provide an answer to causal questions and profile ADRs beyond drug-event combination, to retrieve actionable findings to support enhanced regulatory and clinical management strategies