Exploring novel targeted therapeutic strategies against Acute Myeloid Leukemia cells based on inhibition of bromodomain proteins and CDC20 activity

Acute myeloid leukemia (AML) is a haematological malignancies arising from the accumulation of undifferentiated myeloid progenitors with an uncontrolled proliferation. The genomic landscape of AML revealed that the disease is characterized by high level of heterogeneity and is subjected to clonal evolution driven by selective pressure of chemotherapy. In this study, we investigated the therapeutic effects of the inhibition of BRD4 and CDC20 in vitro and ex vivo. We demonstrated that inhibition of BRD4 with GSK1215101A in AML cell lines was effective under hypoxia. It induced the activation of antioxidant response both, at transcriptomic and metabolomic levels, driven by enrichment of NRF2 pathway under normoxic and hypoxic condition. Moreover, the combined treatment with Omaveloxolone, a drug inducing NRF2 activation and NF-κB inhibition, potentiated the effects on apoptosis and colony forming capacity of stem progenitor cells. Lastly, gene expression profiling data revealed that combination treatment induced major changes in genes related to cell cycle, together with enrichment of cell differentiation pathways and negative regulation of WNT, in normoxia and hypoxia. Regarding CDC20, we observed its up-regulation in AML patients. Treatment with two different inhibitors, Apcin and proTAME, was effective in primary AML cells and in AML cell lines, through induction of apoptosis and mitotic arrest. The lack of correlation between proliferation markers and CDC20 levels in AML cell subpopulations supports the idea of alternative CDC20 functions, independent from its essential role during mitosis. CDC20-KD experiments conducted in AML cell lines revealed a mild effect on apoptosis induction, but no significant change in cell cycle progression. In summary, these results allowed the identification of a new strategy combination to improve the effects of BRD4 inhibition on LSC residing in the BM hypoxic niche, and provide some new evidence regarding the potential role of CDC20 as a new target for AML treatment.

On Reasonable Space and Time Cost Models for the λ-Calculus

Slot and van Emde Boas Invariance Thesis states that a time (respectively, space) cost model is reasonable for a computational model C if there are mutual simulations between Turing machines and C such that the overhead is polynomial in time (respectively, linear in space). The rationale is that under the Invariance Thesis, complexity classes such as LOGSPACE, P, PSPACE, become robust, i.e. machine independent. In this dissertation, we want to find out if it possible to define a reasonable space cost model for the lambda-calculus, the paradigmatic model for functional programming languages. We start by considering an unusual evaluation mechanism for the lambda-calculus, based on Girard's Geometry of Interaction, that was conjectured to be the key ingredient to obtain a space reasonable cost model. By a fine complexity analysis of this schema, based on new variants of non-idempotent intersection types, we disprove this conjecture. Then, we change the target of our analysis. We consider a variant over Krivine's abstract machine, a standard evaluation mechanism for the call-by-name lambda-calculus, optimized for space complexity, and implemented without any pointer. A fine analysis of the execution of (a refined version of) the encoding of Turing machines into the lambda-calculus allows us to conclude that the space consumed by this machine is indeed a reasonable space cost model. In particular, for the first time we are able to measure also sub-linear space complexities. Moreover, we transfer this result to the call-by-value case. Finally, we provide also an intersection type system that characterizes compositionally this new reasonable space measure. This is done through a minimal, yet non trivial, modification of the original de Carvalho type system.

Una proposta di edizione digitale semantica della vita di Federico da Montefeltro di Vespasiano da Bisticci

Il patrimonio culturale è l’espressione della comunità a cui si riferisce e il digitale può essere un valido strumento per raccontare le storie relative ai beni culturali affinché siano, non solo studiati, ma anche recepiti nel loro significato più profondo da più pubblici. L’inserimento di testi manoscritti sul web utilizzando le tecnologie dei Linked Data facilitano la fruizione del testo da parte dell’utente non specializzato e la creazione di strumenti per la ricerca. La proposta di digitalizzazione della tesi ha come oggetto la vita di Federico da Montefeltro scritta da Vespasiano da Bisticci utilizzando i vocabolari schema.org, FOAF e Relationship per la marcatura del testo e i Content Management System per la pubblicazione dei dati. In questo modo sarà possibile avere un sito web in cui potrà essere curato anche l’aspetto grafico seguendo le regole della user experience e dell’information achitecture per valorizzare le figure del duca di Urbino e del cartolaio fiorentino.

A novel hybrid thermochemical-biological refinery integrated with power-to-X approach for obtaining biopolymers

In this study, a novel hybrid thermochemical-biological refinery integrated with power-to-x approach was developed for obtaining biopolymers (namely polyhydroxyalkanoates, PHA). Within this concept, a trilogy process schema comprising of, (i) thermochemical conversion via integrated pyrolysis-gasification technologies, (ii) anaerobic fermentation of the bioavailable products obtained through either thermochemistry or water-electrolysis for volatile fatty acids (VFA) production, (iii) and VFA-to-PHA bioconversion via an original microaerophilic-aerobic process was developed. During the first stage of proposed biorefinery where lignocellulosic (wooden) biomass was converted into, theoretically fermentable products (i.e. bioavailables) which were defined as syngas and water-soluble fraction of pyrolytic liquid (WS); biochar as a biocatalyst material; and a dense-oil as a liquid fuel. Within integrated pyrolysis - gasification process, biomass was efficiently converted into fermentable intermediates representing up to 66% of biomass chemical energy content in chemical oxygen demand (COD) basis. In the secondary stage, namely anaerobic fermentation for obtaining VFA rich streams, three different downstream process were investigated. First fermentation test was acidogenic bioconversion of WS materials obtained through pyrolysis of biomass within an original biochar-packed bioreactor, it was sustained up to 0.6 gCOD/L-day volumetric productivity (VP). Second, C1 rich syngas materials as the gaseous fraction of pyrolysis-gasification stage, was fermented within a novel char-based biofilm sparger reactor (CBSR), where up to 9.8 gCOD/L-day VP was detected. Third was homoacetogenic bioconversion within the innovative power-to-x pathway for obtaining commodities via renewable energy sources. More specifically, water-electrolysis derived H2 and CO2 as a primary greenhouse gas was successfully bio-utilized by anaerobic mixed cultures into VFA within CBSR system (VP: 18.2 gCOD/L-day). In the last stage of the developed biorefinery schema, VFA is converted into biopolymers within a new continuous microaerophilic-aerobic microplant, where up to 60% of PHA containing sludges was obtained.

Valutazione cinematica complessiva, in vivo e sotto carico, di un modello protesico di caviglia a 3 componenti.

Nonostante le importanti ricadute che gli impianti protesici di caviglia hanno nella qualità della vita dei pazienti che si sottopongono ad intervento di sostituzione articolare, le reali proprietà biomeccaniche e cinematiche in-vivo e sotto carico degli impianti protesici sono state scarsamente studiate e descritte in letteratura. Lo scopo di questa trattazione è quella di valutare la cinematica protesica complessiva, in vivo, attraverso l’utilizzo dell’Analisi Radiostereometrica model-based (MB-RSA) e di ulteriori metodiche clinico-strumentali. La valutazione cinematica è stata permessa dall’analisi della posizione degli impianti attraverso la MB-RSA. Tra gli obiettivi secondari, i pazienti sono stati valutati clinicamente mediante AOFAS Ankle-Hindfoot score e SF-36, mediante full-body gait analysis con sensori inerziali e valutazione posturale-stabilometrica mediante Y Balance Test e workstation dedicata Delos DPPS. I pazienti sottoposti ad iter completo con valutazione clinica e strumentale a fine follow-up sono risultati 18 (2 drop-out). Il ROM complessivo a catena cinetica chiusa ha evidenziato una dorsi-plantarflessione complessiva media di 19.84°. Gli score clinici hanno mostrato tutti un netto miglioramento nel post-operatorio. La gait analysis ha evidenziato uno schema del passo composto dai tre principali spike e compatibile con schemi fisiologici. Dal punto di vista cinematico, i risultati angolari MB-RSA ricavati durante questo lavoro di tesi evidenziano tutti e 6 i gradi di libertà, dato coerente con la mobilità di una caviglia nativa. Valori di articolarità differenti sono stati registrati mediante sensori inerziali. Infine, in una valutazione cinematica complessiva, le possibili implicazioni sul bilanciamento posturale e propriocettivo presente nelle caviglie artrosiche e successivamente sottoposte a sostituzione protesica totale sono ampiamente descritte e discusse. I dati raccolti in questo lavoro di tesi rappresentano il risultato di una valutazione cinematica complessiva, e potranno aiutare a definire una tipologia di soggetto artrosico in cui i risultati siano verosimilmente migliori ed eventualmente a migliorare design e strumentari futuri.

Ethics in the flesh: formalizing moral values in embodied cognition

Values are beliefs or principles that are deemed significant or desirable within a specific society or culture, serving as the fundamental underpinnings for ethical and socio-behavioral norms. The objective of this research is to explore the domain encompassing moral, cultural, and individual values. To achieve this, we employ an ontological approach to formally represent the semantic relations within the value domain. The theoretical framework employed adopts Fillmore’s frame semantics, treating values as semantic frames. A value situation is thus characterized by the co-occurrence of specific semantic roles fulfilled within a given event or circumstance. Given the intricate semantics of values as abstract entities with high social capital, our investigation extends to two interconnected domains. The first domain is embodied cognition, specifically image schemas, which are cognitive patterns derived from sensorimotor experiences that shape our conceptualization of entities in the world. The second domain pertains to emotions, which are inherently intertwined with the realm of values. Consequently, our approach endeavors to formalize the semantics of values within an embodied cognition framework, recognizing values as emotional-laden semantic frames. The primary ontologies proposed in this work are: (i) ValueNet, an ontology network dedicated to the domain of values; (ii) ISAAC, the Image Schema Abstraction And Cognition ontology; and (iii) EmoNet, an ontology for theories of emotions. The knowledge formalization adheres to established modeling practices, including the reuse of semantic web resources such as WordNet, VerbNet, FrameNet, DBpedia, and alignment to foundational ontologies like DOLCE, as well as the utilization of Ontology Design Patterns. These ontological resources are operationalized through the development of a fully explainable frame-based detector capable of identifying values, emotions, and image schemas generating knowledge graphs from from natural language, leveraging the semantic dependencies of a sentence, and allowing non trivial higher layer knowledge inferences.

Incompressible limit and well-posedness of PDE models of tissue growth

Both compressible and incompressible porous medium models are used in the literature to describe the mechanical aspects of living tissues. Using a stiff pressure law, it is possible to build a link between these two different representations. In the incompressible limit, compressible models generate free boundary problems where saturation holds in the moving domain. Our work aims at investigating the stiff pressure limit of reaction-advection-porous medium equations motivated by tumor development. Our first study concerns the analysis and numerical simulation of a model including the effect of nutrients. A coupled system of equations describes the cell density and the nutrient concentration and the derivation of the pressure equation in the stiff limit was an open problem for which the strong compactness of the pressure gradient is needed. To establish it, we use two new ideas: an L3-version of the celebrated Aronson-Bénilan estimate, and a sharp uniform L4-bound on the pressure gradient. We further investigate the sharpness of this bound through a finite difference upwind scheme, which we prove to be stable and asymptotic preserving. Our second study is centered around porous medium equations including convective effects. We are able to extend the techniques developed for the nutrient case, hence finding the complementarity relation on the limit pressure. Moreover, we provide an estimate of the convergence rate at the incompressible limit. Finally, we study a multi-species system. In particular, we account for phenotypic heterogeneity, including a structured variable into the problem. In this case, a cross-(degenerate)-diffusion system describes the evolution of the phenotypic distributions. Adapting methods recently developed in the context of two-species systems, we prove existence of weak solutions and we pass to the incompressible limit. Furthermore, we prove new regularity results on the total pressure, which is related to the total density by a power law of state.