Studio di fattibilita’ per lo sfruttamento geotermico delle gallerie del Brennero

Il calore contenuto in profondità negli ammassi rocciosi può essere estratto attraverso un sistema geotermico che prevede l’inserimento di tubazioni in corrispondenza del rivestimento del tunnel, all'interno del quale circola un fluido termovettore che assorbe calore dalle pareti circostanti. Il caso di studio analizzato è la Galleria di Mules, un tunnel scavato in metodo tradizionale all'interno del Granito di Bressanone, che funge come unica finestra di accesso sul lato italiano alla Galleria di Base del Brennero (BBT). Essa si sviluppa in direzione ovest-est per una lunghezza pari circa a 1780 m. In fase di esercizio. Attraverso una caratterizzazione geologica e idrogeologica dell’area di interesse, prove di laboratorio su campioni e rilevazioni delle temperature all’interno della galleria, è stato possibile delineare un quadro geotermico dell’area di interesse. I dati raccolti hanno permesso di ricavare un modello 3D delle temperature dell’area e, attraverso un’apposita procedura di calcolo, quantificare il potenziale energetico estraibile dal tratto di galleria considerato. Sulla base dei risultati ottenuti, è stato realizzato uno schema dettagliato della disposizione del circuito sorgente, adattato sul progetto definitivo del rivestimento interno alla Galleria di Mules. In assenza di potenziali utenze termiche nelle vicinanze del portale di accesso, si è ipotizzato di destinare la risorsa geotermica ad una pavimentazione stradale dotata di sistema snow and ice melting. La pavimentazione permetterà il collegamento fra la strada SS12 e l’imbocco del tunnel. E’ stata effettuata una stima dei costi di investimento dell’intero sistema a pompa di calore e, sulla base del fabbisogno energetico dell’utenza considerata, sono stati valutati i costi di esercizio, confrontandoli con altre possibili soluzioni. Lo studio ha dimostrato la fattibilità tecnico-economica di soluzioni di questo tipo e si pone come primo passo per approfondimenti futuri.

Comportamento fuori piano di pareti in muratura rinforzate con FRCM

Nella presente Tesi è affrontata l’analisi sperimentale e teorica del comportamento di pareti in muratura rinforzate con FRCM e sollecitate da azioni di taglio fuori piano. Lo schema statico adottato per i campioni sperimentati consiste in uno schema appoggio-appoggio, mentre le forze esterne di taglio sono state applicate secondo uno schema di carico a quattro punti. Durante il corso della prova, i pannelli murari sono inoltre stati soggetti ad un carico di precompressione verticale costante, che simula l’effetto della presenza del solaio in un edificio in muratura. Dopo una descrizione teorica delle principali caratteristiche dei materiali compositi e dei loro costituenti, all’interno della Tesi sono richiamati alcuni studi scientifici relativi al comportamento fuori piano di elementi strutturali rinforzati con FRCM. In seguito vengono presentati i materiali impiegati per la campagna sperimentale e le prove di caratterizzazione meccanica eseguite. Vengono poi riportati i risultati sperimentali delle prove a taglio fuori piano in termini di spostamenti, di deformazioni e di scorrimenti, affrontando infine un confronto tra i risultati ottenuti per i campioni esaminati e riportando alcune considerazioni circa la strumentazione impiegata. L’ultima parte della Tesi è dedicata all’analisi teorica delle pareti. Viene proposto un modello teorico per stimare la resistenza fornita dai muri rinforzati, ipotizzando tre possibili modalità di rottura: rottura a trazione della fibra, rottura per distacco tra FRCM e supporto in muratura e rottura per delaminazione interna. Infine, viene riportata la modellazione agli elementi finiti svolta mediante il codice di calcolo MidasFea, che consente di attribuire ai materiali legami costitutivi adeguati per la modellazione di strutture in muratura, cogliendone il comportamento non lineare e il progressivo danneggiamento.

Aspects of supergeometry in locally covariant quantum field theory

In questa tesi vengono presentati i piu recenti risultati relativi all'estensione della teoria dei campi localmente covariante a geometrie che permettano di descrivere teorie di campo supersimmetriche. In particolare, si mostra come la definizione assiomatica possa essere generalizzata, mettendo in evidenza le problematiche rilevanti e le tecniche utilizzate in letteratura per giungere ad una loro risoluzione. Dopo un'introduzione alle strutture matematiche di base, varieta Lorentziane e operatori Green-iperbolici, viene definita l'algebra delle osservabili per la teoria quantistica del campo scalare. Quindi, costruendo un funtore dalla categoria degli spazio-tempo globalmente iperbolici alla categoria delle *-algebre, lo stesso schema viene proposto per le teorie di campo bosoniche, purche definite da un operatore Green-iperbolico su uno spazio-tempo globalmente iperbolico. Si procede con lo studio delle supervarieta e alla definizione delle geometrie di background per le super teorie di campo: le strutture di super-Cartan. Associando canonicamente ad ognuna di esse uno spazio-tempo ridotto, si introduce la categoria delle strutture di super-Cartan (ghsCart) il cui spazio-tempo ridotto e globalmente iperbolico. Quindi, si mostra, in breve, come e possibile costruire un funtore da una sottocategoria di ghsCart alla categoria delle super *-algebre e si conclude presentando l'applicazione dei risultati esposti al caso delle strutture di super-Cartan in dimensione 2|2.

Progettazione del Sistema di Gestione dei Risultati Elettorali del Comune di Cesena

Nel Comune di Cesena è presente un sistema di gestione dei risultati elettorali che si avvale di una base di dati per memorizzare le informazioni sui seggi, sui partiti, sui candidati, e sui risultati da loro ottenuti, ma il software in uso manca di funzionalità avanzate che permettano di eseguire correttamente raffronti fra diverse elezioni, di tenere traccia di cambiamenti nelle parti più statiche dei dati, di identificare univocamente un soggetto anche se è presente più volte con nomi diversi. In questo contesto si inserisce la progettazione del nuovo Sistema di Gestione dei Risultati Elettorali; in primo luogo è stata necessaria una fase di analisi del sistema attuale per capirne le funzionalità e caratteristiche a livello di database, quali fossero le sue mancanze e quali dati venivano memorizzati da usare come base concettuale di partenza per il nuovo sistema. Si è poi passati alla fase di progettazione vera e propria del nuovo sistema perciò è stato prima necessario strutturare la nuova base di dati; con l’aiuto di diagrammi ER si è stabilito quali fossero le entità necessarie al funzionamento del database, siamo passati poi attraverso una normalizzazione dei diagrammi fino ad ottenere uno schema fisico che indicasse tutte le tabelle e abbiamo scelto di utilizzare la suite DBMS Oracle per la creazione del database. Si è poi scelto di utilizzare il linguaggio di scripting PHP per realizzare l’interfaccia per consentire l’accesso al sistema da parte di molteplici client, prestando particolare attenzione al procedimento di inserimento dei dati preliminari di un’elezione, cioè tutti quei dati che vengono inseriti prima del giorno della votazione che includono i seggi che verranno utilizzati, i partiti e i candidati che si contenderanno il voto degli elettori. Anche in questo caso, al termine dell’implementazione, si è eseguita un’ampia fase di test per assicurarsi che l’utente inserisca in maniera corretta solo ed esclusivamente i dati necessari.

NDRG1/2 expression is inhibited in primary acute myeloid leukemia

Expression of N-myc downregulated gene 1 (NDRG1) is associated with growth arrest and differentiation of tumor cells. In hematopoietic cells, NDRG1 was identified in a screen for differentiation-related genes in human myelomonocytic leukemic U937 cells. In the present study, we found significantly higher NDRG1 mRNA levels in granulocytes of healthy donors than in primary acute myeloid leukemia (AML) cells. Another NDRG family member, NDRG2, was significantly higher expressed in normal macrophages compared to primary AML cells. Moreover, NDRG1 mRNA levels increased in two acute promyelocytic leukemia (APL) patients as well as in NB4 and HT93 APL cells upon all-trans retinoic acid (ATRA) therapy. In line with these observations, silencing of NDRG1 diminished neutrophil differentiation of leukemic cell lines. In conclusion, we found an association of low NDRG1 levels with an immature cell phenotype and provide evidence that NDRG1 is functionally involved in neutrophil maturation.

Unfolded protein response suppresses CEBPA by induction of calreticulin in acute myeloid leukaemia

The unfolded protein response (UPR) is triggered by the accumulation of misfolded proteins within the endoplasmic reticulum (ER). The role of the UPR during leukemogenesis is unknown so far. Here, we studied the induction of mediators of the UPR in leukaemic cells of AML patients. Increased expression of the spliced variant of the X-box binding protein 1 (XBP1s) was detected in 17.4% (16 of 92) of AML patients. Consistent with activated UPR, this group also had increased expression of ER-resident chaperones such as the 78 kD glucose-regulated protein (GRP78) and of calreticulin. Conditional expression of calreticulin in leukaemic U937 cells was found to increase calreticulin binding to the CEBPA mRNA thereby efficiently blocking translation of the myeloid key transcription factor CEBPA and ultimately affecting myeloid differentiation. Consequently, leukaemic cells from AML patients with activated UPR and thus increased calreticulin levels showed in fact suppressed CEBPA protein expression. We identified two functional ER stress response elements (ERSE) in the calreticulin promoter. The presence of NFY and ATF6, as well as an intact binding site for YY1 within these ERSE motifs were essential for mediating sensitivity to ER stress and activation of calreticulin. Thus, we propose a model of the UPR being activated in a considerable subset of AML patients through induction of calreticulin along the ATF6 pathway, thereby ultimately suppressing CEBPA translation and contributing to the block in myeloid differentiation.

PU.1 is regulated by NF-kappaB through a novel binding site in a 17 kb upstream enhancer element

The majority of patients with acute myeloid leukemia (AML) still die of their disease, and novel therapeutic concepts are needed. Timely expression of the hematopoietic master regulator PU.1 is crucial for normal development of myeloid and lymphoid cells. Targeted disruption of an upstream regulatory element (URE) located several kb upstream in the PU.1 promoter decreases PU.1 expression thereby inducing AML in mice. In addition, suppression of PU.1 has been observed in specific subtypes of human AML. Here, we identified nuclear factor-kappaB (NF-kappaB) to activate PU.1 expression through a novel site within the URE. We found sequence variations of this particular NF-kappaB site in 4 of 120 AML patients. These variant NF-kappaB sequences failed to mediate activation of PU.1. Moreover, the synergistic activation of PU.1 together with CEBPB through these variant sequences was also lost. Finally, AML patients with such variant sequences had suppressed PU.1 mRNA expression. This study suggests that changes of a single base pair in a distal element critically affect the regulation of the tumor suppressor gene PU.1 thereby contributing to the development of AML.

Epigallocatechin-3-gallate induces cell death in acute myeloid leukaemia cells and supports all-trans retinoic acid-induced neutrophil differentiation via death-associated protein kinase 2

Acute promyelocytic leukaemia (APL) patients are successfully treated with all-trans retinoic acid (ATRA). However, concurrent chemotherapy is still necessary and less toxic therapeutic approaches are needed. Earlier studies suggested that in haematopoietic neoplasms, the green tea polyphenol epigallocatechin-3-gallate (EGCG) induces cell death without adversely affecting healthy cells. We aimed at deciphering the molecular mechanism of EGCG-induced cell death in acute myeloid leukaemia (AML). A significant increase of death-associated protein kinase 2 (DAPK2) levels was found in AML cells upon EGCG treatment paralleled by increased cell death that was significantly reduced upon silencing of DAPK2. Moreover, combined ATRA and EGCG treatment resulted in cooperative DAPK2 induction and potentiated differentiation. EGCG toxicity of primary AML blasts correlated with 67 kDa laminin receptor (67LR) expression. Pretreatment of AML cells with ATRA, causing downregulation of 67LR, rendered these cells resistant to EGCG-mediated cell death. In summary, it was found that (i) DAPK2 is essential for EGCG-induced cell death in AML cells, (ii) ATRA and EGCG cotreatment significantly boosted neutrophil differentiation, and 67LR expression correlates with susceptibility of AML cells to EGCG. We thus suggest that EGCG, by selectively targeting leukaemic cells, may improve differentiation therapies for APL and chemotherapy for other AML subtypes.

CLEC5A (MDL-1) is a novel PU.1 transcriptional target during myeloid differentiation

C-type lectin domain family 5, member A (CLEC5A), also known as myeloid DNAX activation protein 12 (DAP12)-associating lectin-1 (MDL-1), is a cell surface receptor strongly associated with the activation and differentiation of myeloid cells. CLEC5A associates with its adaptor protein DAP12 to activate a signaling cascade resulting in activation of downstream kinases in inflammatory responses. Currently, little is known about the transcriptional regulation of CLEC5A. We identified CLEC5A as one of the most highly induced genes in a microarray gene profiling experiment of PU.1 restored myeloid PU.1-null cells. We further report that CLEC5A expression is significantly reduced in several myeloid differentiation models upon PU.1 inhibition during monocyte/macrophage or granulocyte differentiation. In addition, CLEC5A mRNA expression was significantly lower in primary acute myeloid leukemia (AML) patient samples than in macrophages and granulocytes from healthy donors. Moreover, we found activation of a CLEC5A promoter reporter by PU.1 as well as in vivo binding of PU.1 to the CLEC5A promoter. Our findings indicate that CLEC5A expression in monocyte/macrophage and granulocytes is regulated by PU.1.

Knowing the future: partial foreknowledge effects on the programming of prosaccades and antisaccades

Foreknowledge about the demands of an upcoming trial may be exploited to optimize behavioural responses. In the current study we systematically investigated the benefits of partial foreknowledge--that is, when some but not all aspects of a future trial are known in advance. For this we used an ocular motor paradigm with horizontal prosaccades and antisaccades. Predictable sequences were used to create three partial foreknowledge conditions: one with foreknowledge about the stimulus location only, one with foreknowledge about the task set only, and one with foreknowledge about the direction of the required response only. These were contrasted with a condition of no-foreknowledge and a condition of complete foreknowledge about all three parameters. The results showed that the three types of foreknowledge affected saccadic efficiency differently. While foreknowledge about stimulus-location had no effect on efficiency, task foreknowledge had some effect and response-foreknowledge was as effective as complete foreknowledge. Foreknowledge effects on switch costs followed a similar pattern in general, but were not specific for switching of the trial attribute for which foreknowledge was available. We conclude that partial foreknowledge has a differential effect on efficiency, most consistent with preparatory activation of a motor schema in advance of the stimulus, with consequent benefits for both switched and repeated trials.

Deregulated expression of Kruppel-like factors in acute myeloid leukemia

The known participation of Kruppel-like transcription factors (KLF) in cellular differentiation prompted us to investigate their expression in acute myeloid leukemia (AML) blast cells that are typically blocked in their differentiation. We determined the expression patterns of KLFs with a putative role in myeloid differentiation in a large cohort of primary AML patient samples, CD34+ progenitor cells and granulocytes from healthy donors. We found that KLF2, KLF3, KLF5 and KLF6 are significantly lower expressed in AML blast and CD34+ progenitor cells as compared to normal granulocytes. Moreover, we found markedly increased KLF levels in acute promyelocytic leukemia patients who received oral ATRA. Accordingly, we observed a strong induction of KLF5/6 upon ATRA-treatment in NB4 and HT93 APL but not in ATRA-resistant NB4-R cells. Lastly, knocking down KLF5 or KLF6 in NB4 cells significantly attenuated neutrophil differentiation. In conclusion, we found a significant repression of KLF transcription factors in primary AML samples as compared to mature neutrophils and further show that KLF5 and KLF6 are functionally involved in neutrophil differentiation of APL cells.

Inhibition of the miR-143/145 cluster attenuated neutrophil differentiation of APL cells

MicroRNAs can influence hematopoietic cell lineage commitment and aberrant expression of hematopoietic miRNAs contributes to AML pathology. We found that miR-143 and miR-145 expression is significantly repressed in primary AML patient samples as compared to neutrophils of healthy donors. Further analysis revealed impaired neutrophil differentiation of APL cells upon inhibition of miR-145 expression. Lastly, we identified p73 as transcriptional regulator of miR-143/145 during neutrophil differentiation of APL cells. Our data suggest that low miR-145 levels in APL, possibly due to aberrant expression of p73 transcription factors, contribute to the differentiation block seen in this disease.

Favorable effect of priming with granulocyte colony-stimulating factor in remission induction of acute myeloid leukemia restricted to dose-escalation of cytarabine

The clinical value of chemotherapy sensitization of acute myeloid leukemia (AML) with G-CSF priming has remained controversial. Cytarabine is a key constituent of remission induction chemotherapy. The effect of G-CSF priming has not been investigated in relationship with variable dose levels of cytarabine. We randomized 917 AML patients to receive G-CSF (456 patients) or no G-CSF (461 patients) at the days of chemotherapy. In the initial part of the study, 406 patients were also randomized between 2 cytarabine regimens comparing conventional-dose (199 patients) versus escalated-dose (207 patients) cytarabine in cycles 1 and 2. We found that patients after induction chemotherapy plus G-CSF had similar overall survival (43% vs 40%, P = .88), event-free survival (37% vs 31%, P = .29), and relapse rates (34% vs 36%, P = .77) at 5 years as those not receiving G-CSF. However, patients treated with the escalated-dose cytarabine regimen benefited from G-CSF priming, with improved event-free survival (P = .01) and overall survival (P = .003), compared with patients without G-CSF undergoing escalated-dose cytarabine treatment. A significant survival advantage of sensitizing AML for chemotherapy with G-CSF was not apparent in the entire study group, but it was seen in patients treated with escalated-dose cytarabine during remission induction. The HOVON-42 study is registered under The Netherlands Trial Registry (www.trialregister.nl) as #NTR230.

Cytarabine dose for acute myeloid leukemia

Cytarabine (ara-C) is an important drug in the treatment of acute myeloid leukemia (AML). High-dose cytarabine (2000 to 3000 mg per square meter of body-surface area) is toxic but results in higher rates of relapse-free survival than does the conventional dose of 100 to 400 mg per square meter. Intermediate dose levels have not been thoroughly evaluated.