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Anticancer drug discovery using artificial intelligence: an application in pharmacological activity prediction
Get PDFHematological cancers are a heterogeneous family of diseases that can be divided into leukemias, lymphomas, and myelomas, often called “liquid tumors”. Since they cannot be surgically removable, chemotherapy represents the mainstay of their treatment. However, it still faces several challenges like drug resistance and low response rate, and the need for new anticancer agents is compelling. The drug discovery process is long-term, costly, and prone to high failure rates. With the rapid expansion of biological and chemical "big data", some computational techniques such as machine learning tools have been increasingly employed to speed up and economize the whole process. Machine learning algorithms can create complex models with the aim to determine the biological activity of compounds against several targets, based on their chemical properties. These models are defined as multi-target Quantitative Structure-Activity Relationship (mt-QSAR) and can be used to virtually screen small and large chemical libraries for the identification of new molecules with anticancer activity.
The aim of my Ph.D. project was to employ machine learning techniques to build an mt-QSAR classification model for the prediction of cytotoxic drugs simultaneously active against 43 hematological cancer cell lines. For this purpose, first, I constructed a large and diversified dataset of molecules extracted from the ChEMBL database. Then, I compared the performance of different ML classification algorithms, until Random Forest was identified as the one returning the best predictions. Finally, I used different approaches to maximize the performance of the model, which achieved an accuracy of 88% by correctly classifying 93% of inactive molecules and 72% of active molecules in a validation set. This model was further applied to the virtual screening of a small dataset of molecules tested in our laboratory, where it showed 100% accuracy in correctly classifying all molecules. This result is confirmed by our previous in vitro experiments
A cohomological approach to Ruelle-Pollicott resonances and speed of mixing of Anosov diffeomorphisms
Get PDFGiven a transitive Anosov diffeomorphism on a closed manifold it is known that, for smooth enough observables, the system is mixing w.r.t. the measure of maximal entropy. Therefore, it makes sense to investigate the speed of decay of correlations and to look for the so-called Ruelle-Pollicott resonances, in order to determine a complete asymptotics for the decay of correlations. In this thesis we are able to find the first terms of that asymptotics and to prove an estimate for the speed of decaying of correlations. The proof is based on a surprising connection between the action of a transfer operator on suitable anisotropic Banach spaces of currents and the action induced by the Anosov map on the de Rham cohomology
From images to signs: Cretan Hieroglyphic and Linear A in context
Get PDFThis dissertation adopts a multidisciplinary approach to investigate graphical and formal features of Cretan Hieroglyphic and Linear A. Drawing on theories which understand inscribed artefacts as an interplay of materials, iconography, and texts, I combine archaeological and philological considerations with statistical and experimental observations. The work is formulated on three key-questions.
The first deals with the origins of Cretan Hieroglyphic. After providing a fresh view on Prepalatial seals chronology, I identify a number of forerunners of Hieroglyphic signs in iconographic motifs attested among the Prepalatial glyptic and material culture. I further identified a specific style-group, i.e., the ‘Border and Leaf Complex’, as the decisive step towards the emergence of the Hieroglyphic graphic repertoire.
The second deals with the interweaving of formal, iconographical, and epigraphic features of Hieroglyphic seals with the sequences they bear and the contexts of their usage. By means of two Correspondence Analyses, I showed that the iconography on seals in some materials and shapes is closer to Cretan Hieroglyphics, than that on the other ones. Through two Social Network Analyses, I showed that Hieroglyphic impressions, especially at Knossos, follow a precise sealing pattern due to their shapes and sequences. Furthermore, prisms with a high number of inscribed faces adhere to formal features of jasper ones. Finally, through experimental engravings, I showed differences in cutting rates among materials, as well as the efficiency of abrasives and tools unearthed within the Quartier Mu.
The third question concerns overlaps in chronology, findspots and signaries between Cretan Hieroglyphic and Linear A. I discussed all possible earliest instances of both scripts and argued for some items datable to the MM I-IIA period. I further provide an insight into the Hieroglyphic-Linear A dubitanda and criteria for their interpretation. Finally, I suggest four different patterns in the creation and diversification of the two signaries
Researches in the field of 'ius emphyteuticum' on 'meliorationes, quae graeco vocabulo emponemata dicuntur'
Get PDFLe presenti ricerche indagano la disciplina delle «meliorationes, quae graeco vocabulo emponemata dicuntur» nell’ambito dell’enfiteusi privata giustinianea, pervenendo, a seguito della ricostruzione della nozione di «emponemata», a una interpretazione di C. 4.66.3 (a. 530) secondo la quale questa costituzione non implicherebbe – anche in ragione del confronto testuale con Nov. 64 (a. 538), in materia di «misthosis» – una deroga al principio «superficies solo cedit» e – con riferimento alla fattispecie della loro alienazione – farebbe del termine «meliorationes» un uso condizionale e metonimico, volto a enucleare – nell’ambito delle diverse possibilità di trasferimento «inter vivos» dell’enfiteusi – il caso (oggetto di speciale normazione) della «venditio» per la sola ipotesi in cui sul fondo enfiteutico fossero intervenute «meliorationes» tali da poter essere qualificate come «emponemata».The present researches investigate the discipline of «meliorationes, quae graeco vocabulo emponemata dicuntur» in the context of Justinian private emphyteusis, arriving, following the reconstruction of the notion of «emponemata», at an interpretation of C. 4.66.3 (a. 530) according to which this constitution would not imply – also because of the textual comparison with Nov. 64 (a. 538), on the subject of «misthosis» – a derogation from the principle «superficies solo cedit» and – with reference to the case of their alienation – would make conditional and metonymic use of the term «meliorationes» aimed at enucleating – within the sphere of the different possibilities of transfer «inter vivos» of emphyteusis – the case (subject to special regulation) of the «venditio» for the sole hypothesis in which «meliorationes» – that could be qualified as «emponemata» – had intervened on the emphyteutic fund
Monitoring of New Psychoactive Substances in the hair of patients with a history of addiction. Evaluation of the public health impact.
Get PDFIntroduction. The term New Psychoactive Substances (NPS) encompasses a broad category of drugs which have become available on the market in recent years and whose illicit use for recreational purposes has recently exploded. The analysis of NPS usually requires mass spectrometry based techniques. The aim of our study was to define the preva-lence of NPS consumption in patients with a history of drug addiction followed by Public Services for Pathological Addictions, with the purpose of highlighting the effective presence of NPS within the area of Bologna and evaluating their association with classical drugs of abuse (DOA).
Materials and methods. Sustained by literature, a multi-analyte UHPLC-MS/MS method for the identification of 127 NPS (phenethylamines, arylcyclohexylamines, synthetic opioids, tryptamines, synthetic cannabinoids, synthetic cathinones, designer benzodiazepines) and 15 classic drugs of abuse (DOA) in hair samples was developed and validated according to International Guidelines [112]. Samples pretreatment consisted of washing steps and overnight incubation at 45°C in an acid mixture of methanol and water. After cooling, supernatant were injected into the chromatographic system coupled with a tandem mass spectrometry detector.
Results. Successful validation was achieved for almost all of the compounds. The method met all the required technical parameters. LOQ was set from 4 to 80 pg/mg The developed method was applied to 107 cases (85 males and 22 females) of clinical interest. Out of 85 hair samples resulting positive to classical drugs of abuse, NPS were found in twelve (8 male and 4 female).
Conclusion. The present methodology represents an easy, low cost, wide-panel method for the de-tection of 127 NPS and 15 DOA in hair samples. Such multi-analyte methods facilitates the study of the prevalence of drugs abused that will enable the competent control authorities to obtain evi-dence-based reports regarding the critical spread of the threat represented by NPS
Fluorogenic hyaluronan-based probe: characterization and use in advanced microscopy
Get PDFAmong all, the application of nanomaterials in biomedical research and most recently in the environmental one has opened the fields of nanomedicine and nanoremediation. Sensing methods based on fluorescence optical probe are generally requested for their selectivity, sensitivity. However, most imaging methods in literature rely on a fluorescent covalent labelling of the system. Therefore, the main aim of this project was to synthetise a biocompatible fluorogenic hyaluronan probe (HA) polymer functionalised with a rhomadine B (RB) moieties and study its behaviour as an optical probe with different materials with microscopy techniques. A derivatization of HA with RB (HA-RB) was successfully obtained providing a photophysical characterization showing a particular fluorescence mechanism of the probe. Firstly, we tested the interaction with different lab-grade micro and nanoplastics in water. Thanks to the peculiar photophysical behaviour of the probe nanoplastics can be detected with confocal microscopy and more interestingly their nature can be discriminated based on the fluorescence lifetime decay with FLIM microscopy. After, the interaction of a model plant derived metabolic enzyme GAPC1 undergoing oxidative-triggered aggregation was explored with the HA-RB. We highlighted the probe interaction with the protein even at early stage of the kinetic. Moreover, nanoparticle tracking analysis (NTA) experiment demonstrates that the probe is in fact able to interact with the small pre-aggregates in the early stage of the aggregation kinetic. Ultimately, we focused on the possibility to apply the probe in a super resolution microscopy technique, PALM, exploiting its aspecific interaction to characterize the surface topography of PTFE polydisperse microplastics. Optimal conditions were reached at high concentration of the probe (70 nM) where 0.5-5 nM is always advisable for this technique. Thanks to the polymeric nature and fluorescence mechanism of the probe, this technique was able to reveal features of PTFE surface under the diffraction limit (< 250 nm)
Search for same-sign top quark pairs with the ATLAS detector at the LHC
Get PDFIn this thesis, a search for same-sign top quark pairs produced according to the Standard Model Effective Field Theory (SMEFT) is presented.
The analysis is carried out within the ATLAS Collaboration using collision data at a center-of-mass energy of TeV, collected by the ATLAS detector during the Run 2 of the Large Hadron Collider, corresponding to an integrated luminosity of fb.
Three SMEFT operators are considered in the analysis, namely , , and .
The signal associated to same-sign top pairs is searched in the dilepton channel, with the top quarks decaying via , leading to a final state signature composed of a pair of high-transverse momentum same-sign leptons and -jets.
Deep Neural Networks are employed in the analysis to enhance sensitivity to the different SMEFT operators and to perform signal-background discrimination.
This is the first result of the ATLAS Collaboration concerning the search for same-sign top quark pairs production in proton-proton collision data at TeV, in the framework of the SMEFT
Coworking spaces: thriving and organizing in the new world of work
Get PDFThe present Ph.D. thesis proposes three studies on coworking spaces to understand how they foster thriving and organizing in the new world of work. The first study maps and analyzes the thematic structure and evolution of the academic debate that has emerged around coworking spaces in recent years. In doing so, it conducts a science mapping analysis of 351 publications on coworking spaces to detect and visualize key themes in the literature and their co-occurrence with subthemes. The second study proposes an interpretive review of 98 publications from multiple disciplines to shed light on how coworking spaces emerge as sites of organizing for professionals who are not formally connected to one another. It suggests five dimensions that articulate coworking spaces as sites of organizing – ‘materiality,’ ‘temporality,’ ‘affect,’ ‘identity,’ and ‘formalization.’ This study aims to go beyond the community-related understanding of coworking that has characterized most scholarly attention, instead focusing on coworking spaces’ organizational character. The third study investigates what drives thriving at work for remote workers in coworking spaces. In doing so, it acknowledges the potential complex set of interrelationships underpinning thriving at work and mobilizes complexity theory and qualitative comparative analysis to uncover six different, yet equifinal, configurations of antecedents driving remote workers’ thriving in coworking spaces
Models and algorithms for real-world optimization problems
Get PDFThis thesis deals with efficient solution of optimization problems of practical interest.
The first part of the thesis deals with bin packing problems. The bin packing problem (BPP) is one of the oldest and most fundamental combinatorial optimiza- tion problems.
The bin packing problem and its generalizations arise often in real-world ap- plications, from manufacturing industry, logistics and transportation of goods, and scheduling.
After an introductory chapter, I will present two applications of two of the most natural extensions of the bin packing: Chapter 2 will be dedicated to an application of bin packing in two dimension to a problem of scheduling a set of computational tasks on a computer cluster, while Chapter 3 deals with the generalization of BPP in three dimensions that arise frequently in logistic and transportation, often com- plemented with additional constraints on the placement of items and characteristics of the solution, like, for example, guarantees on the stability of the items, to avoid potential damage to the transported goods, on the distribution of the total weight of the bins, and on compatibility with loading and unloading operations.
The second part of the thesis, and in particular Chapter 4 considers the Trans- mission Expansion Problem (TEP), where an electrical transmission grid must be expanded so as to satisfy future energy demand at the minimum cost, while main- taining some guarantees of robustness to potential line failures. These problems are gaining importance in a world where a shift towards renewable energy can impose a significant geographical reallocation of generation capacities, resulting in the ne- cessity of expanding current power transmission grids
Power in public art spaces. F(r)ictions, performativity and the generation of counter-hegemonic narratives
Get PDFAbstract
This thesis applies queer theories to the examination of experiences which go beyond queerness. Queer, decolonial, antiracist and feminist new materialist concepts are implemented to the analysis of four case studies dealing with power and art in public spaces. By applying concepts as methodologies, autoethnographic reflections and f(r)ictions as research alternatives, the thesis brings up new diffractive readings from where to perform those scenarios differently. In doing so, the thesis disentangles the historical, material, philosophical, political and disruptive meanings which haunt the four case studies and triggers the artivist potential of their counter-hegemonic narratives