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Integrating omics in prion diseases as a model to explore the strain paradigm in neurodegenerative diseases
Get PDFThis project aims at deepening the understanding of the molecular basis of the phenotypic heterogeneity of prion diseases. Prion diseases represent the first and clearest example of “protein misfolding diseases”, that are all the neurodegenerative diseases caused by the accumulation of misfolded proteins in the central nervous system. In the field of protein misfolding diseases, the term “strain” describes the heterogeneity observed among the same disease in the clinical and pathologic progression, biochemical features of the aggregated protein, conformational memory and pattern of lesions. In this work, the two most common strains of Creutzfeldt-Jakob Disease (CJD), named MM1 and VV2, were analyzed. This thesis investigates the strain paradigm with the production of new multi omic data, and, on such data, appropriate computational analysis combining bioinformatics, data science and statistical approaches was performed. In this work, genomic and transcriptomic profiling allowed an improved characterization of the molecular features of the two most common strains of CJD, identifying multiple possible genetic contributors to the disease and finding several shared impaired pathways between the VV2 strain and Parkinson Disease. On the epigenomic level, the tridimensional chromatin folding in peripheral immune cells of CJD patients at onset and of healthy controls was investigated with Hi-C. While being the first application of this very advanced technology in prion diseases and one of the first in general in neurobiology, this work found a significant and diffuse loss of genomic interactions in immune cells of CJD patients at disease onset, particularly in the PRNP locus, suggesting a possible impairment of chromatin conformation in the disease. The results of this project represent a novelty in the state of the art in this field, both from a biomedical and technological point of view
Investigating interpreter-mediated interaction in the Chinese bilingual courtroom: Analysis based on a multimodal corpus
Get PDFThis research project is based on the Multimodal Corpus of Chinese Court Interpreting (MUCCCI [mutʃɪ]), a small-scale multimodal corpus on the basis of eight authentic court hearings with Chinese-English interpreting in Mainland China. The corpus has approximately 92,500 word tokens in total. Besides the transcription of linguistic and para-linguistic features, utilizing the facial expression classification rules suggested by Black and Yacoob (1995), MUCCCI also includes approximately 1,200 annotations of facial expressions linked to the six basic types of human emotions, namely, anger, disgust, happiness, surprise, sadness, and fear (Black & Yacoob, 1995).
This thesis is an example of conducting qualitative analysis on interpreter-mediated courtroom interactions through a multimodal corpus. In particular, miscommunication events (MEs) and the reasons behind them were investigated in detail. During the analysis, although queries were conducted based on non-verbal annotations when searching for MEs, both verbal and non-verbal features were considered indispensable parts contributing to the entire context. This thesis also includes a detailed description of the compilation process of MUCCCI utilizing ELAN, from data collection to transcription, POS tagging and non-verbal annotation.
The research aims at assessing the possibility and feasibility of conducting qualitative analysis through a multimodal corpus of court interpreting. The concept of integrating both verbal and non-verbal features to contribute to the entire context is emphasized. The qualitative analysis focusing on MEs can provide an inspiration for improving court interpreters’ performances. All the constraints and difficulties presented can be regarded as a reference for similar research in the future
Speed, legislatures and international treaties: Evidence from Mercosur
Get PDFWhat causes faster or slower procedures in the parliaments when considering international treaties? This question motivates the current research, which aims to understand how the nature of coalitions influence the duration of the legislative processes. For this, the analysis covers all the treaties signed by Mercosur between 1991 and 2021 and the internalisation processes in four member states (Argentina, Brazil, Paraguay and Uruguay). It observes how long each parliament took to approve the treaties and which was the effect of political and economic variables. A mixed-methods approach was adopted for the empirical research, combining Survival Analysis, Qualitative Comparative Analysis and Process Tracing. While the quantitative work investigates all the cases, the qualitative study illuminates the enlargement of Mercosur, with in-depth analysis of the Paraguayan approval of the Venezuelan and Bolivian accessions. This study provides important insights into the role of national legislatures in the Latin American regionalism, concluding that the government-opposition cleavage drives the parliamentarians’ behaviour on the topic of regional integration. The study also contributes to the field Mercosur studies with the characterisation of the treaties ratified domestically, by undertaking a longitudinal analysis at the 30th anniversary of the bloc
Technological applications and new methods of performance assessment in water sports
Get PDFNello sport di alto livello l’uso della tecnologia ha raggiunto un ruolo di notevole importanza per l’analisi e la valutazione della prestazione. Negli ultimi anni sono emerse nuove tecnologie e sono migliorate quelle pre-esistenti (i.e. accelerometri, giroscopi e software per l’analisi video) in termini di campionamento, acquisizione dati, dimensione dei sensori che ha permesso la loro “indossabilità” e l’inserimento degli stessi all’interno degli attrezzi sportivi. La tecnologia è sempre stata al servizio degli atleti come strumento di supporto per raggiungere l’apice dei risultati sportivi. Per questo motivo la valutazione funzionale dell’atleta associata all’uso di tecnologie si pone lo scopo di valutare i miglioramenti degli atleti misurando la condizione fisica e/o la competenza tecnica di una determinata disciplina sportiva. L’obiettivo di questa tesi è studiare l’utilizzo delle applicazioni tecnologiche e individuare nuovi metodi di valutazione della performance in alcuni sport acquatici. La prima parte (capitoli 1-5), si concentra sulla tecnologia prototipale chiamata E-kayak e le varie applicazioni nel kayak di velocità. In questi lavori è stata verificata l’attendibilità dei dati forniti dal sistema E-kayak con i sistemi presenti in letteratura. Inoltre, sono stati indagati nuovi parametri utili a comprendere il modello di prestazione del paddler. La seconda parte (capitolo 6), si riferisce all’analisi cinematica della spinta verticale del pallanuotista, attraverso l’utilizzo della video analisi 2D, per l’individuazione delle relazioni Forza-velocità e Potenza-velocità direttamente in acqua. Questo studio pilota, potrà fornire indicazioni utili al monitoraggio e condizionamento di forza e potenza da svolgere direttamente in acqua. Infine la terza parte (capitoli 7-8), si focalizza sull’individuazione della sequenza di Fibonacci (sequenza divina) nel nuoto a stile libero e a farfalla. I risultati di questi studi suggeriscono che il ritmo di nuotata tenuto durante le medie/lunghe distanze gioca un ruolo chiave. Inoltre, il livello di autosomiglianza (self-similarity) aumenta con la tecnica del nuoto.In high-level sports, technology has achieved a role of considerable importance for the analysis and performance assessment. In recent years, the developments in new technologies and the improvements in previous ones (i.e. accelerometers, gyroscopes, and software for video analysis) in terms of sample rate, data acquisition, and sensor size, allowed the "wearability" of new sensor systems and their insertion into the sport equipment. Technology has always been at the service of athletes as a support tool to achieve the top in sports results. For this reason, the functional assessment of the athlete associated with the use of technologies aims to assess the improvements of athletes by measuring the physical condition and/or technical skills on a specific sport. This thesis aims to study the use of technological applications and identify new methods of performance assessment in some water sports. The first part (chapters 1-5), focuses on the prototype technology called E-kayak and the various applications in flatwater sprint kayaking. Here, the reliability of the data provided by the E-kayak with other systems available in the literature was verified. In addition, new parameters useful for understanding the paddler's performance model were investigated. The second part (chapter 6), refers to the kinematic analysis of the vertical thrust in the waterpolo player, through the use of 2D video analysis, for the identification of the Force-velocity and Power-velocity relationships directly in the water. This pilot study will provide useful information for the monitoring and conditioning of strength and power to be carried out directly in the water. Finally, the third part (chapters 7-8) focuses on identifying the Fibonacci sequence (divine sequence) in crawl and butterfly swimming styles. The results of these studies suggest that the swimming pace maintained during medium/long distances plays a key role. Furthermore, the level of self-similarity increases with the swimming technique
Contrast-enhanced ultrasound from research to clinical practice: diagnosis of hepatocellular carcinoma with CEUS LI-RADS system and with software of quantification of tissue perfusion
Get PDFIl carcinoma epatocellulare (HCC) rappresenta il tumore epatico primitivo più comune con una incidenza fino all’85%. È uno dei tumori più frequenti al mondo ed è noto per l’elevata letalità soprattutto in stadio avanzato. La diagnosi precoce attraverso la sorveglianza ecografica è necessaria per migliorare la sopravvivenza dei pazienti a rischio. Il mezzo di contrasto ecografico migliora la sensibilità e la specificità diagnostica dell’ecografia convenzionale. L’ecografia con mezzo di contrasto (contrast-enhanced ultrasound, CEUS) è pertanto considerata una metodica valida per la diagnosi di HCC a livello globale per la sua ottima specificità anche a fronte di una sensibilità subottimale. L’aspetto contrastografico delle lesioni focali epatiche ha portato un team di esperti allo sviluppo del sistema Liver Imaging Reporting and Data System (LI-RADS) con l’obiettivo di standardizzare la raccolta dati e la refertazione delle metodiche di imaging per la diagnosi di HCC. La CEUS è una metodica operatore-dipendente e le discordanze diagnostiche con gli imaging panoramici lasciano spazio a nuove tecniche (Dynamic Contrast Enhanced UltraSound, DCE-US) volte a migliorare l’accuratezza diagnostica della metodica e in particolare la sensibilità. Un software di quantificazione della perfusione tissutale potrebbe essere di aiuto nella pratica clinica per individuare il wash-out non visibile anche all’occhio dell’operatore più esperto. Il nostro studio ha due obiettivi: 1) validare il sistema CEUS LI-RADS nella diagnosi di carcinoma epatocellulare in pazienti ad alto rischio di HCC usando come gold-standard l’istologia quando disponibile oppure metodiche di imaging radiologico accettate da tutte le linee guida (tomografia computerizzata o risonanza magnetica con aspetto tipico) eseguite entro quattro settimane dalla CEUS; 2) valutare l’efficacia di un software di quantificazione della perfusione tissutale nel riscontro di wash-out per la diagnosi di HCC in CEUS.Hepatocellular carcinoma (HCC) is the most common primary liver cancer with an incidence of up to 85%. It is one of the most frequent cancers in the world and is known for its high lethality, especially in the advanced stage. Early diagnosis through ultrasound surveillance is needed to improve survival of at-risk patients. The ultrasound contrast agent improves the sensitivity and diagnostic specificity of conventional ultrasound. Contrast-enhanced ultrasound (CEUS) is therefore considered a valid method for diagnosing HCC globally due to its excellent specificity even if its sensitivity is suboptimal. The aspect of focal hepatic lesions on CEUS led a team of experts to develop the Liver Imaging Reporting and Data System (LI-RADS) with the aim of standardizing data collection and reporting of imaging methods for the diagnosis of HCC. CEUS is an operator-dependent examination and the diagnostic discrepancies with panoramic imaging leave room for new techniques such as the Dynamic Contrast Enhanced UltraSound (DCE-US) aimed at improving the diagnostic accuracy and in particular the sensitivity of the echography. A tissue perfusion quantification software could be of help in clinical practice to identify the wash-out that is not visible even to the eye of the most experienced operator. Our study has two objectives: 1) to validate the CEUS LI-RADS system in the diagnosis of hepatocellular carcinoma in patients at high risk of HCC using histology as a gold standard when available or radiological imaging methods accepted by all guidelines (computed tomography or magnetic resonance imaging) performed within four weeks from CEUS; 2) evaluate the efficacy of a tissue perfusion quantification software in the detection of wash-out for the diagnosis of HCC in CEUS
Mapping new non-genetic dependencies in malignant pleural mesothelioma
Get PDFMalignant Pleural Mesothelioma (MPM) is a very aggressive cancer whose incidence is growing worldwide. MPM escapes the classical models of carcinogenesis and lacks a distinctive genetic fingerprint, keeping obscure the molecular events that lead to tumorigenesis. This severely impacts on the limited therapeutic options and on the lack of specific biomarkers, concurring to make MPM one of the deadliest cancers.
Here we combined a functional genome-wide loss of function CRISPR/Cas9 screening with patients’ transcriptomic and clinical data, to identify genes essential for MPM progression. Besides, we explored the role of non-coding RNAs to MPM progression by analysing gene expression profiles and clinical data from the MESO-TCGA dataset.
We identified TRIM28 and the lncRNA LINC00941 as new vulnerabilities of MPM, associated with disease aggressiveness and bad outcome of patients. TRIM28 is a multi-domain protein involved in many processes, including transcription regulation. We showed that TRIM28 silencing impairs MPM cells’ growth and clonogenicity by blocking cells in mitosis. RNA-seq profiling showed that TRIM28 loss abolished the expression of major mitotic players. Our data suggest that TRIM28 is part of the B-MYB/FOXM1-MuvB complex that specifically drives the activation of mitotic genes, keeping the time of mitosis.
In parallel, we found LINC00941 as strongly associated with reduced survival probability in MPM patients. LINC00941 KD profoundly reduced MPM cells’ growth, migration and invasion. This is accompanied by changes in morphology, cytoskeleton organization and cell-cell adhesion properties. RNA-seq profiling showed that LINC00941 KD impacts crucial functions of MPM, including HIF1α signalling.
Collectively these data provided new insights into MPM biology and demonstrated that the integration of functional screening with patients’ clinical data is a powerful tool to highlight new non-genetic cancer dependencies that associate to a bad outcome in vivo, paving the way to new MPM-oriented targeted strategies and prognostic tools to improve patients risk-based stratification
Myotonic syndromes: analysis of factors with pathogenetic and prognostic significance
Get PDFBackground: The natural history of Myotonic Dystrophy type 1 is largely unclear, longitudinal studies are lacking.
Objectives: to collect clinical and laboratory data, to evaluate sleep disorders, somatic and autonomic skin fibres, neuropsychological and neuroradiological aspects in DM1 patients.
Methods: 72 DM1 patients underwent a standardized clinical and neuroradiological evaluation performed by a multidisciplinary team during 3 years of follow-up.
Results: longer disease duration was associated with higher incidence of conduction disorders and lower ejection fraction; higher CVF values were predictors for a reduced risk of cardiopathy. Lower functional pulmonary values were associated with class of expansion and were negatively associated with disease duration; arterial blood gas parameters were not associated with expansion size, disease duration nor with respiratory function test. Excessive daytime sleepiness was not associated with class of expansion nor with any of the clinical parameters examined. We detected apnoea in a large percentage of patients, without differences between the 3 genetic classes; higher CVF values were predictors for a reduced risk of apnoea. Skin biopsies demonstrated the presence of a subclinical small fibre neuropathy with involvement of the somatic fibres. The pupillometry study showed lower pupil size at baseline and a lower constriction response to light. The most affected neuropsychological domains were executive functions, visuoconstructional, attention and visuospatial tasks, with a worse performance of E1 patients in the visuoperceptual ability and social cognition tasks. MRI study demonstrated a decrease in the volumes of frontal, parietal, temporal, occipital cortices, accumbens, putamen nuclei and a more severe volume reduction of the isthmus cingulate, transverse temporal, superior parietal and temporal gyri in E2 patients.
Discussion: only some clinical parameters could predict the risk of cardiopathy, pulmonary syndrome and sleep disorders, while other clinical aspects proved to be unpredictable, confirming the importance of periodic clinical follow-up of these patients
The FOOT experiment: Trigger and Data Acquisition (TDAQ) development and data analysis
Get PDFHadrontherapy employs high-energy beams of charged particles (protons and heavier ions) to treat deep-seated tumours: these particles have a favourable depth-dose distribution in tissue characterized by a low dose in the entrance channel and a sharp maximum (Bragg peak) near the end of their path. In these treatments nuclear interactions have to be considered: beam particles can fragment in the human body releasing a non-zero dose beyond the Bragg peak while fragments of human body nuclei can modify the dose released in healthy tissues. These effects are still in question given the lack of interesting cross sections data. Also space radioprotection can profit by fragmentation cross section measurements: the interest in long-term manned space missions beyond Low Earth Orbit is growing in these years but it has to cope with major health risks due to space radiation. To this end, risk models are under study: however, huge gaps in fragmentation cross sections data are currently present preventing an accurate benchmark of deterministic and Monte Carlo codes. To fill these gaps in data, the FOOT (FragmentatiOn Of Target) experiment was proposed. It is composed by two independent and complementary setups, an Emulsion Cloud Chamber and an electronic setup composed by several subdetectors providing redundant measurements of kinematic properties of fragments produced in nuclear interactions between a beam and a target.
FOOT aims to measure double differential cross sections both in angle and kinetic energy which is the most complete information to address existing questions. In this Ph.D. thesis, the development of the Trigger and Data Acquisition system for the FOOT electronic setup and a first
analysis of 400 MeV/u 16O beam on Carbon target data acquired in July 2021 at GSI (Darmstadt, Germany) are presented. When possible, a comparison with other available
measurements is also reported.L’adroterapia è una tecnica di radioterapia esterna nella quale vengono utilizzati fasci di ioni (protoni e ioni più pesanti) ad alta energia per il trattamento di tumori profondi: tali particelle hanno una distribuzione dose-profondità nel tessuto molto favorevole, caratterizzata da un basso rilascio di dose nel canale di entrata e un massimo pronunciato (picco di Bragg) vicino alla fine del loro percorso. In tali trattamenti devono essere prese in considerazione anche le interazioni nucleari: le particelle del fascio possono frammentare nel corpo umano rilasciando una dose non nulla oltre il picco di Bragg mentre i frammenti dei nuclei del paziente possono modificare la dose rilasciata nei tessuti sani. L’entità di tali effetti è attualmente oggetto di studio vista l’assenza di misure sulle sezioni d’urto di interesse. Anche il campo della radioprotezione spaziale può trarre benificio da queste misure poiché i rischi per la salute causati dalla radiazione spaziale rimangono un
grande problema da affrontare: per questo motivo si studiano modelli di rischio che attualmente risentono della significativa mancanza di dati sulle sezioni d’urto.
L’esperimento FOOT (FragmentatiOn Of Target) è composto da due apparati indipendenti e complementari, una Emulsion Cloud Chamber e un apparato elettronico composto da alcuni rivelatori che forniscono misure ridondanti delle quantità cinematiche dei frammenti nucleari prodotti dalle interazioni tra il fascio ed il bersaglio.
FOOT ha l’obiettivo di misurare le sezioni d’urto differenziali sia in angolo che in energia cinetica, informazioni fondamentali per rispondere ai problemi aperti. In questa tesi sono presentati sia lo sviluppo del sistema di trigger e acquisizione dati (TDAQ) per l’apparato elettronico dell’esperimento sia una prima analisi dei dati del fascio di 16O a 400 MeV/u su un bersaglio di carbonio acquisiti a luglio 2021 presso il GSI (Darmstadt, Germania) oltre ad un confronto, quando possibile, con altre misure attualmente disponibili
Re-building for regeneration. A model for urban peripheries
Get PDFIn Italia, quasi il 90% delle abitazioni esistenti sono state edificate prima degli anni Settanta del Novecento, se consideriamo la tipologia costruttiva, le normative per la sicurezza strutturale in ambito sismico e il comportamento energetico, ne deriva che la maggior parte non risponde agli standard vigenti. A questo si aggiunge la consapevolezza che il patrimonio residenziale costruito in quel periodo, e che occupa le prime periferie delle città, non si presta per sua natura costitutiva ad essere oggetto di interventi di riqualificazione che siano giustificabili in termini di costi-benefici dal punto di vista economico e per ottimizzazione ingegneristica.
È opportuno ripensare piani e programmi di rinnovamento non circoscritti alle categorie di risanamento, efficientamento, manutenzione, adeguamento, ma che siano in grado di assumere in positivo il tema della sostituzione secondo il paradigma del ri-costruire per ri-generare per sviluppare strategie a medio-lungo termine per soddisfare un quadro esigenziale-prestazionale coerente con la legislazione europea, in termini di sicurezza, efficienza e impatto ambientale, e promuovere la pianificazione e lo sviluppo sostenibile delle città.
L’edilizia circolare è qui intesa come un’attività finalizzata alla costruzione e gestione degli edifici all’interno di un ecosistema economico basato sulla circolarità dei processi.
L’obiettivo della ricerca è duplice: (i) metodologico, rivolto alla formalizzazione di un modello innovativo d’intervento associato ai principi della circolarità e basato sulla conoscenza approfondita del patrimonio esistente; e (ii) progettuale, prevede la progettazione di un prototipo di unità abitativa e l’applicazione del modello ad un caso di studio, che viene assunto come applicazione sperimentale ad un contesto reale e momento conclusivo del processo. La definizione di una matrice valutativa consente di formulare indicazioni operative nella fase precedente l’intervento per rendere espliciti, attraverso un indice sintetico di supporto decisionale, i criteri su cui fondare le scelte tra le due macro-categorie di intervento (demolizione con ricostruzione o rinnovo).In Italy, almost 90% of the existing dwellings were built before the 1970s; moreover, considering the type of construction and the regulatory framework for seismic structural safety and energy behaviour, we note that most do not meet the criteria laid down in the regulation. The truth is that almost all residential constructions built in the periphery in the second half of the twentieth century in Italy are not suited, due to their constitutive nature, to be subject to feasible renovation measures in terms of cost-benefit and economic sustainability, and engineering optimisation.
Renovation programmes should be rethought and not limited to reconditioning, efficiency, maintenance, or adaptation, but able to adopt replacement interventions according to the “re-construction for re-generation” paradigm, which should provide a basis for a medium-long term development strategy aiming at meeting a requirement and performance framework consistent with the European legislation, in terms of safety, efficiency and environmental impact, and promote the sustainable planning of cities.
The term “circular construction” herein identifies an activity aimed at buildings construction and management within an economic ecosystem based on circular processes.
The objective of the research is twofold: (i) methodological, aimed at creating an innovative model of the building process associated with circular economy principles and based on a solid knowledge of the existing stock; and (ii) project-specific, aimed at designing a housing unit prototype and applying this model to a case study used as an experimental application to a real context and as the final step of the process. The definition of an evaluation matrix is envisaged to formulate operational indications to be followed prior to the intervention to specify, through the use of a summary index of decision support, the criteria for the choice between the two macro-categories of intervention (demolition and reconstruction or renovation)
A machine learning based method to detect genomic imbalances exploiting X chromosome exome reads
Get PDFWhole Exome Sequencing (WES) is rapidly becoming the first-tier test in clinics, both thanks to its
declining costs and the development of new platforms that help clinicians in the analysis and
interpretation of SNV and InDels. However, we still know very little on how CNV detection could
increase WES diagnostic yield. A plethora of exome CNV callers have been published over the years,
all showing good performances towards specific CNV classes and sizes, suggesting that the
combination of multiple tools is needed to obtain an overall good detection performance. Here we
present TrainX, a ML-based method for calling heterozygous CNVs in WES data using EXCAVATOR2
Normalized Read Counts. We select males and females’ non pseudo-autosomal chromosome X
alignments to construct our dataset and train our model, make predictions on autosomes target
regions and use HMM to call CNVs. We compared TrainX against a set of CNV tools differing for the
detection method (GATK4 gCNV, ExomeDepth, DECoN, CNVkit and EXCAVATOR2) and found that
our algorithm outperformed them in terms of stability, as we identified both deletions and
duplications with good scores (0.87 and 0.82 F1-scores respectively) and for sizes reaching the
minimum resolution of 2 target regions. We also evaluated the method robustness using a set of
WES and SNP array data (n=251), part of the Italian cohort of Epi25 collaborative, and were able to
retrieve all clinical CNVs previously identified by the SNP array. TrainX showed good accuracy in
detecting heterozygous CNVs of different sizes, making it a promising tool to use in a diagnostic
setting