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Development of advanced methods for the simulation of the reacting mixture formation in internal combustion engines with the use of machine learning algorithms
Get PDFBesides increasing the share of electric and hybrid vehicles, in order to comply with more stringent environmental protection limitations, in the mid-term the auto industry must improve the efficiency of the internal combustion engine and the well to wheel efficiency of the employed fuel. To achieve this target, a deeper knowledge of the phenomena that influence the mixture formation and the chemical reactions involving new synthetic fuel components is mandatory, but complex and time intensive to perform purely by experimentation. Therefore, numerical simulations play an important role in this development process, but their use can be effective only if they can be considered accurate enough to capture these variations.
The most relevant models necessary for the simulation of the reacting mixture formation and successive chemical reactions have been investigated in the present work, with a critical approach, in order to provide instruments to define the most suitable approaches also in the industrial context, which is limited by time constraints and budget evaluations. To overcome these limitations, new methodologies have been developed to conjugate detailed and simplified modelling techniques for the phenomena involving chemical reactions and mixture formation in non-traditional conditions (e.g. water injection, biofuels etc.). Thanks to the large use of machine learning and deep learning algorithms, several applications have been revised or implemented, with the target of reducing the computing time of some traditional tasks by orders of magnitude. Finally, a complete workflow leveraging these new models has been defined and used for evaluating the effects of different surrogate formulations of the same experimental fuel on a proof-of-concept GDI engine model.Besides increasing the share of electric and hybrid vehicles, in order to comply with more stringent environmental protection limitations, in the mid-term the auto industry must improve the efficiency of the internal combustion engine and the well to wheel efficiency of the employed fuel. To achieve this target, a deeper knowledge of the phenomena that influence the mixture formation and the chemical reactions involving new synthetic fuel components is mandatory, but complex and time intensive to perform purely by experimentation. Therefore, numerical simulations play an important role in this development process, but their use can be effective only if they can be considered accurate enough to capture these variations.
The most relevant models necessary for the simulation of the reacting mixture formation and successive chemical reactions have been investigated in the present work, with a critical approach, in order to provide instruments to define the most suitable approaches also in the industrial context, which is limited by time constraints and budget evaluations. To overcome these limitations, new methodologies have been developed to conjugate detailed and simplified modelling techniques for the phenomena involving chemical reactions and mixture formation in non-traditional conditions (e.g. water injection, biofuels etc.). Thanks to the large use of machine learning and deep learning algorithms, several applications have been revised or implemented, with the target of reducing the computing time of some traditional tasks by orders of magnitude. Finally, a complete workflow leveraging these new models has been defined and used for evaluating the effects of different surrogate formulations of the same experimental fuel on a proof-of-concept GDI engine model
Contribution of rare damaging variants in Autism Spectrum Disorder
Get PDFAutism Spectrum Disorder (ASD) is a heterogeneous and highly heritable neurodevelopmental disorder with a complex genetic architecture, consisting of a combination of common low-risk and more penetrant rare variants.
This PhD project aimed to explore the contribution of rare variants in ASD susceptibility through NGS approaches in a cohort of 106 ASD families including 125 ASD individuals.
Firstly, I explored the contribution of inherited rare variants towards the ASD phenotype in a girl with a maternally inherited pathogenic NRXN1 deletion. Whole exome sequencing of the trio family identified an increased burden of deleterious variants in the proband that could modulate the CNV penetrance and determine the disease development.
In the second part of the project, I investigated the role of rare variants emerging from whole genome sequencing in ASD aetiology. To properly manage and analyse sequencing data, a robust and efficient variant filtering and prioritization pipeline was developed, and by its application a stringent set of rare recessive-acting and ultra-rare variants was obtained. As a first follow-up, I performed a preliminary analysis on de novo variants, identifying the most likely deleterious variants and highlighting candidate genes for further analyses.
In the third part of the project, considering the well-established involvement of calcium signalling in the molecular bases of ASD, I investigated the role of rare variants in voltage-gated calcium channels genes, that mainly regulate intracellular calcium concentration, and whose alterations have been correlated with enhanced ASD risk. Specifically, I functionally tested the effect of rare damaging variants identified in CACNA1H, showing that CACNA1H variation may be involved in ASD development by additively combining with other high risk variants.
This project highlights the challenges in the analysis and interpretation of variants from NGS analysis in ASD, and underlines the importance of a comprehensive assessment of the genomic landscape of ASD individuals
Dissecting the role of IGF2BP3 in the stress-adaptive response and in intercellular communication in Ewing Sarcoma.
Get PDFTumor microenvironment has emerged as key factor influencing tumor progression and metastatization. In this context, small vesicles produced by cancer cells can influence the fate of their surroundings via the horizontal transfer of specific molecular cargos. Ewing Sarcoma, the second most common bone tumor in young patients, presents early metastasis associated to worse prognosis. The RNA binding protein Insulin-like Growth Factor 2 mRNA Binding Protein 3 (IGF2BP3) exerts a pro-oncogenic role associated with metastasis formation and worse prognosis in Ewing Sarcoma. Our aim was to investigate the still unexplored role of IGF2BP3 in the stress-adaptive response to tumor microenvironment and in the interactions between Ewing Sarcoma cells.
Hypoxia is a major feature of Ewing Sarcoma microenvironment and we demonstrated that IGF2BP3
can direct the CXCR4-mediated migratory response to CXCL12 in Ewing Sarcoma cells subjected to
oxygen deprivation. We also discovered that the interaction between IGF2BP3 and CXCR4 is regulated through CD164 and which colocalize at plasma membrane level, upon CXCL12 exposure. Interestingly, high IGF2BP3 levels in Ewing Sarcoma metastatic lesions positively correlated with the expression of both CD164 and CXCR4, indicating the IGF2BP3/CD164/CXCR4 oncogenic axis as a critical modulator of Ewing Sarcoma metastatic progression. We demonstrated for the first time that IGF2BP3 is loaded into Ewing Sarcoma derived exosomes, accordingly to its cellular levels. We discovered that IGF2BP3+ exosomes carry high levels of IGF2BP3-client mRNAs involved in cellular migration, CD164 and IGF1R, and, by transferring this cargo, sustain the migratory abilities of receiving cells, induce a sharp up-regulation of CD164, CXCR4 and IGF1R and enhance the activation of AKT/mTOR and ERK down-stream signalling pathways. We demostrated that the pro-tumorigenic role of IGF2BP3 is not only exerted at cellular level, but that intercellular communication is crucial in the context of Ewing Sarcoma microenvironment
A genome editing approach to the study of Parvovirus B19
Get PDFParvovirus B19 (B19V) is a ssDNA virus, with a 5596 nt long genome encapsidated within an icosahedral capsid with a diameter of 22 nm. Viral proteins are subdivided into structural and non-structural: the main non-structural one is the NS1, while the 2 structural proteins VP1 and VP2 assemble originating the capsid shell.
B19V tropism is mainly limited to erythroid progenitor cells (EPCs), however, virus can be detected in several districts persisting in tissues possibly lifelong. The virus can induce anemia and erythroid aplasia. Therapeutic strategies are only symptomatic, so the search for antivirals is strongly active, with screenings showing the activity in vitro of different compounds like hydroxyurea, cidofovir and brincidofovir.
In the first project, a functional minigenome of B19V was developed, able to express only the NS1 protein. This minigenome proved able to replicate and express the NS1 at levels comparable to unmodified clones. Furthermore, the ability of this minigenome to complement the function of NS1-deficient genomes was demonstrated, thus providing a proof-of-concept of B19V genome editing possibility and, at the same time, a useful tool to study the NS1 protein also as an antiviral target.
In the second project I addressed the interplay between B19V and the cellular restriction factor APOBEC3B (A3B), a cytidine deaminase acting on ssDNA, whose footprint on B19V genome was proved by a bioinformatic sequence analysis performed by the hosting lab. To understand whether A3B still exerts activity and a potential antiviral effect on B19V, the UT7/EpoS1 cells were transduced with lentiviral vectors to silence A3B expression, then used as a model to study viral behavior. No significant role of A3B on B19V was demonstrated, in agreement with the hypothesis of viral adaptation to this cellular restriction factor; anyway, virus ability to alter A3B expression would deserve further investigations
The interactional perspective of conference interpreting: Italian-Chinese consecutive interpreting in conferences with minor degree of formality
Get PDFLa nascita dell’interpretazione di conferenza è strettamente legata a storici incontri diplomatici e ai congressi di istituzioni internazionali di grande rilievo. Tuttavia, oggi, nell’epoca della globalizzazione, ci si riunisce sempre più per la condivisione di conoscenze e per motivi personali, anche in contesti meno formalizzati. Sebbene, in quanto conferenza, le norme interazionali continuino a vincolare il meccanismo dei turni di parola, in tali circostanze tra l’oratore e chi lo ascolta si instaurano maggiore sintonia e attenzione reciproca attraverso molteplici mezzi comunicativi, verbali e non-verbali.
Il presente studio, posizionandosi nella prospettiva dell’analisi discorsiva e della comunicazione multimodale, ha come obiettivo quello di verificare se la presenza dell’interprete modifichi la relazione interpersonale caratterizzata dal senso di reciprocità tra chi enuncia e chi ascolta, e se sì, quali siano le nuove dinamiche comunicative che emergono. A tal fine, sono stati reperiti filmati di nove conferenze con minor grado di formalità dove era previsto lo svolgimento dell’interpretazione consecutiva tra l’italiano e il cinese e, relativamente a questi, sono state eseguite dapprima due fasi di valutazione preliminare: la prima prevedeva la raccolta e l’analisi delle informazioni di base riguardanti lo svolgimento dei nove eventi e i relativi partecipanti; la seconda consisteva nell’esame contrastivo tra i sistemi linguistico-culturali italiano e cinese. In seguito all’acquisizione delle informazioni contestuali e circostanziali, si è proceduto all’analisi qualitativa dei casi di studio di interazione tra l’interprete e gli altri partecipanti. A tal fine, soni stati esaminati non solo gli interventi linguistici, ma anche le attività non-verbali. Nonostante la molteplicità delle dinamiche osservate, è stato possibile riconoscere una tendenza secondo cui l’interprete stabilisce relazioni di carattere dialogico sia con i partecipanti presenti sul palco, ovvero l’oratore e il moderatore, che con il pubblico presente agli eventi analizzati.The birth of conference interpreting is closely related to important diplomatic meetings in modern history and congresses of major international institutions. Nowadays, with the intensification of globalization, however, an increasing number of encounters with the purpose of sharing personal interests and knowledge are held within less formalized contexts. In such circumstances, notwithstanding conference communicative norms still exist, mutual understanding can be achieved between speakers and listeners through multiple interactional channels, including both verbal and non-verbal ones.
Setting off from Discourse Analysis and Multimodal Communication, this thesis aims to investigate whether interpreters’ presence modifies the interpersonal relationship of reciprocity between speakers and listeners, and if so, which type of communicative dynamics emerges accordingly. To this end, video recordings of Italian-Chinese consecutive interpreting from nine conferences characterized by a minor degree of formality were found online. Based on these data, two preliminary assessments were carried out thereupon, namely the examination of the background information concerning the above-mentioned events and participants involved, and a contrastive description regarding Italian and Chinese linguistic-cultural systems. Relying on contextual information and resources, the interaction between interpreters and other participants were analyzed qualitatively, including both verbal and non-verbal activities. In spite of the variety of dynamics observed, a tendency emerges, whereby interpreters attempted to establish dialogical relationships respectively with participants on stage (speakers and moderators), and audiences who attend the conference
Design and synthesis of E3 ligase RNF5 inhibitors as innovative strategy to trigger mutant CFTR rescue in Cystic Fibrosis
Get PDFIn Cystic Fibrosis (CF) the deletion of phenylalanine 508 (F508del) in the CFTR anion channel is associated to misfolding and defective gating of the mutant protein. Among the known proteins involved in CFTR processing, one of the most promising drug target is the ubiquitin ligase RNF5, which normally promotes F508del-CFTR degradation. In this context, a small molecule RNF5 inhibitor is expected to chemically mimic a condition of RNF5 silencing, thus preventing mutant CFTR degradation and causing its stabilization and plasma membrane trafficking. Hence, by exploiting a virtual screening (VS) campaign, the hit compound inh-2 was discovered as the first-in-class inhibitor of RNF5. Evaluation of inh-2 efficacy on CFTR rescue showed that it efficiently decreases ubiquitination of mutant CFTR and increases chloride current in human primary bronchial epithelia.
Based on the promising biological results obtained with inh-2, this thesis reports the structure-based design of potential RNF5 inhibitors having improved potency and efficacy. The optimization of general synthetic strategies gave access to a library of analogues of the 1,2,4-thiadiazol-5-ylidene inh-2 for SAR investigation. The new analogues were tested for their corrector activity in CFBE41o- cells by using the microfluorimetric HS-YFP assay as a primary screen. Then, the effect of putative RNF5 inhibitors on proliferation, apoptosis and the formation of autophagic vacuoles was evaluated. Some of the new analogs significantly increased the basal level of autophagy, reproducing RNF5 silencing effect in cell. Among them, one compound also displayed a greater rescue of the F508del-CFTR trafficking defect than inh-2.
Our preliminary results suggest that the 1,2,4-thiadiazolylidene could be a suitable scaffold for the discovery of potential RNF5 inhibitors able to rescue mutant CFTRs. Biological tests are still ongoing to acquire in-depth knowledge about the mechanism of action and therapeutic relevance of this unprecedented pharmacological strategy
DNA methylation and Allogeneic Stem Cell Trasplantation
Get PDFIl trapianto di cellule staminali emopoietiche rappresenta la terapia di scelta per numerose patologie
ematologiche. Tuttavia, la mortalità da trapianto (non relapse mortality-NRM), ha limitato per lungo tempo il suo utilizzo in pazienti di età >65 anni. L’età non può più essere considerata una
controindicazione assoluta al trapianto e il suo utilizzo in fasce di età un tempo ritenute non idonee è in sensibile aumento. La NRM è legata a tre ordini di complicanze: immunologiche (malattia del trapianto contro l’ospite, Graft versus-Host Disease -GVHD-), infettive e tossiche. La tossicità d’organo è direttamente correlata alla intensità del condizionamento che quindi viene ridotta in caso di comorbidità e nel paziente anziano. Tuttavia, ridurre l’intensità del condizionamento significa anche aumentare il rischio di ripresa della malattia ematologica di base e quindi tale aggiustamento
deve essere fatto in funzione di indici di invecchiamento e di comorbidità, al fine di non ridurre la
potenzialità curativa del trapianto. Per valutare le comorbidità abbiamo uno score altamente predittivo (Hematopoietic Cell Transplant-Comorbidity Index, di Sorror), mentre per valutare l’invecchiamento c’è una grande necessità clinica di marcatori innovativi di età biologica.
Il presente lavoro ha l’obiettivo di valutare, nei pazienti sottoposti a trapianto allogenico di
cellule staminali emopoietiche per tutte le indicazioni ematologiche, lo stato di metilazione del DNA, indice di età biologica. Lo scopo è di correlare l’epigenoma al rischio trapiantologico del singolo individuo.Allogeneic hematopoietic stem cell transplantation (HSCT) is a well-established therapy for several life-threatening hematological disorders, mostly malignancies. However, non-relapse mortality (NRM) has limited its use in patients aged over 65 years. Nowadays age cannot be considered an absolute contraindication for this treatment and the use of transplantation, in patient groups once considered unsuitable, is increasing significantly. NRM is due to three types of complications: immunological (graft versus host disease), infectious and toxic. Organ toxicity is directly related to the intensity of conditioning which is therefore reduced in case of comorbidities and in elderly patients. However, reducing the intensity of chemotherapy also means increasing the risk of relapse of the underlying haematological disease and therefore this adjustment must consider aging and comorbidity indexes in order not to reduce the curative potential of the transplant. To evaluate comorbidities we have a highly predictive score (the Comorbidity Index Score by Sorror, HCT-CI), while to evaluate aging there is a great clinical need to apply innovative biological age markers.
The present work aims to evaluate the state of DNA methylation, a biological age index, in the setting of patients undergoing allogeneic haematopoietic stem cell transplantation for all haematological indication. The aim is also to correlate the epigenome with the transplant risk of the single individual
From Genesis to Disposal of ELTIF. A new and “unsettled” step in the composite framework of collective saving management
Get PDFLa presente trattazione concerne gli European long-term investment fund, disciplinati dal regolamento UE 2015/760 del 29 aprile 2015, meglio noti come ELTIF, di cui si è inteso indagare i molteplici aspetti che attengono all’operatività degli stessi, dalla genesi sino alla fase della liquidazione.
Trattandosi di uno dei più recenti tasselli della composita disciplina europea del risparmio gestito, si è ritenuto opportuno anzitutto prendere le mosse dall’evoluzione della regolamentazione, domestica e comunitaria, della gestione collettiva del risparmio, la quale rappresenta la “cornice” normativa di riferimento entro cui si colloca il veicolo in discorso.
Definito il percorso evolutivo della disciplina de qua, si è posta quindi l’attenzione sulla regolamentazione degli ELTIF che, pur migliorabile sotto diversi profili, rappresenta un significativo passo in avanti nel senso della costruzione dell’Unione dei mercati di capitali e del rilancio dell’economia europea. In particolare, l’indagine ha riguardato anzitutto i connotati della nuova fattispecie (carattere europeo, orizzonte temporale di lungo periodo, illiquidità). L’analisi dei tratti fisiognomici è stata funzionale non solo a verificare se essi, nella loro peculiarità, siano o meno idonei a definire un tipo a sé stante di prodotto, ma altresì a valutare in che termini essi producano un effetto conformativo sulla disciplina del prodotto stesso, specie con riferimento alla fase dell’investimento e del disinvestimento.
Con l’intento di vagliare l’opportunità di interventi sul dato normativo che mirino ad accrescere l’attrattività degli ELTIF, si è volta quindi l’attenzione alla fase finale della vita del fondo, in quanto l’esiguità della disciplina dettata con riferimento alla liquidazione si espone ad applicazioni dubbie che, in larga parte, lasciano spazio all’autonomia regolamentare del prodotto e, dunque, all’applicazione di discipline nazionali disomogenee; e ciò specie con riferimento a una peculiare ipotesi di liquidazione promossa dagli investitori in conseguenza del mancato soddisfacimento della richiesta di rimborso avanzata.This paper focuses on the European Long-Term Investment Fund, regulated under EU Regulation 2015/760 of April 29, 2015, better known as ELTIFs, of which it was intended to investigate the many aspects of their operations, from genesis to disposal.
Since this regulation is one of the latest steps of the composite European Framework of Collective Saving Management, it was considered appropriate to start from the evolution of domestic and European regulations on collective asset management, which represents the regulatory framework for ELTIFs.
This paper focuses on the regulation of ELTIFs which, although it can be improved in many aspects, represents a significant step forward in the construction of The Capital Markets Union and Europe’s economic recovery. Firstly, the investigation is concentrated on the characteristics of the new case (European nature, long-term, illiquidity).
The analysis of the physiognomic features has aimed to verify if ELTIFs are able to define a new type of fund and then to evaluate how their features produce an effect on the rules of the product itself, especially the rules of investment and disinvestment.
In addition, the attention has therefore focused on the final period of the fund’s life. In fact, the few rules about the disposal of ELTIFs could create some application issues, giving way to different national rules; it can especially happen when the investors may request the winding down of an ELTIF if their redemption requests have not been satisfied
Criminal Law and End of Life: Assisted Suicide and Euthanasia.
Get PDFIl presente elaborato si propone di esaminare il tema del fine vita, con specifico riferimento al suicidio assistito e all’eutanasia. Dopo aver evidenziato la netta distinzione tra rifiuto/rinuncia del trattamento sanitario anche salva vita, aiuto al suicidio ed eutanasia, ci si sofferma, in primo luogo, sull’analisi della legge n. 219/2017, rubricata “Norme in materia di consenso informato e di disposizioni anticipate di trattamento”, che riconosce la massima ampiezza all’autodeterminazione terapeutica nell’ambito della relazione medico-paziente. In secondo luogo, si esamina il tema del suicidio assistito, soffermandosi sulle pronunce della giurisprudenza costituzionale e di merito. Successivamente, in una prospettiva comparata, viene fornita un’ampia analisi delle discipline della
morte medicalmente assistita attualmente vigente in diversi ordinamenti. Infine, si esamina il tema dell’eutanasia, in particolare concentrandosi sulla donazione di organi post eutanasia, sul rischio della slippery slope e sulla necessità di tutelare i soggetti vulnerabili.This thesis aims to examine the topic of the end of life, with specific reference to assisted suicide and euthanasia. After highlighting the clear distinction between refusal of medical treatments, suicide aid and euthanasia, we focus, first of all, on the analysis of Act no. 219/2017, which recognizes the maximum extent to therapeutic self-determination in the context of physician-patient relationship. Secondly, the subject of assisted suicide is examined, focusing on the jurisprudence. Subsequently, assuming a comparative perspective, a broad analysis of the disciplines of medically assisted death of various States is examined. Finally, the issue of euthanasia is analyzed, focusing in particular on post-euthanasia organ donation, on the risk of the slippery slope and on the need to protect vulnerable individuals
Smart Textile Sensors for Healthcare Monitoring
Get PDFWearable electronic textiles are an emerging research field playing a pivotal role among several different technological areas such as sensing, communication, clothing, health monitoring, information technology, and microsystems. The possibility to realise a fully-textile platform, endowed with various sensors directly realised with textile fibres and fabric, represents a new challenge for the entire research community.
Among several high-performing materials, the intrinsically conductive poly(3,4-ethylenedioxythiophene) (PEDOT), doped with poly(styrenesulfonic acid) (PSS), or PEDOT:PSS, is one of the most representative and utilised, having an excellent chemical and thermal stability, as well as reversible doping state and high conductivity.
This work relies on PEDOT:PSS combined with sensible materials to design, realise, and develop textile chemical and physical sensors. In particular, chloride concentration and pH level sensors in human sweat for continuous monitoring of the wearer's hydration status and stress level are reported. Additionally, a prototype smart bandage detecting the moisture level and pH value of a bed wound to allow the remote monitoring of the healing process of severe and chronic wounds is described. Physical sensors used to monitor the pressure distribution for rehabilitation, workplace safety, or sport tracking are also presented together with a novel fully-textile device able to measure the incident X-ray dose for medical or security applications where thin, comfortable, and flexible features are essential. Finally, a proof-of-concept for an organic-inorganic textile thermoelectric generator that harvests energy directly from body heat has been proposed.
Though further efforts must be dedicated to overcome issues such as durability, washability, power consumption, and large-scale production, the novel, versatile, and widely encompassing area of electronic textiles is a promising protagonist in the upcoming technological revolution