Complexity of N-Myc transcriptional function in childhood neuroblastoma

Myc is a transcription factor that can activate transcription of several hundreds genes by direct binding to their promoters at specific DNA sequences (E-box). However, recent studies have also shown that it can exert its biological role by repressing transcription. Such studies collectively support a model in which c-Myc-mediated repression occurs through interactions with transcription factors bound to promoter DNA regions but not through direct recognition of typical E-box sequences. Here, we investigated whether N-Myc can also repress gene transcription, and how this is mechanistically achieved. We used human neuroblastoma cells as a model system in that N-MYC amplification/over-expression represents a key prognostic marker of this tumour. By means of transcription profile analyses we could identify at least 5 genes (TRKA, p75NTR, ABCC3, TG2, p21) that are specifically repressed by N-Myc. Through a dual-step-ChIP assay and genetic dissection of gene promoters, we found that N-Myc is physically associated with gene promoters in vivo, in proximity of the transcription start site. N-Myc association with promoters requires interaction with other proteins, such as Sp1 and Miz1 transcription factors. Furthermore, we found that N-Myc may repress gene expression by interfering directly with Sp1 and/or with Miz1 activity (i.e. TRKA, p75NTR, ABCC3, p21) or by recruiting Histone Deacetylase 1 (Hdac1) (i.e. TG2). In vitro analyses show that distinct N-Myc domains can interact with Sp1, Miz1 and Hdac1, supporting the idea that Myc may participate in distinct repression complexes by interacting specifically with diverse proteins. Finally, results show that N-Myc, through repressed genes, affects important cellular functions, such as apoptosis, growth, differentiation and motility. Overall, our results support a model in which N-Myc, like c-Myc, can repress gene transcription by direct interaction with Sp1 and/or Miz1, and provide further lines of evidence on the importance of transcriptional repression by Myc factors in tumour biology.

Reconceptualising professional development in early childhood education. A study on teachers' professionalism carried out in Bologna province.

The research undertaken for this doctoral thesis explores the issue of teachers professionalism within pre-school institutions. The issue of early childhood professionalism has become increasingly important in the academic debate over the last decade as it is documented by a growing body of research published on the topic both nationally (Contini & Manini, 2007; Bondioli & Ferrari, 2004) and internationally (Peeters, 2008; Urban & Dalli, 2008; Urban, 2010). The study presented in this thesis aims at investigating teachers’ conceptualisations of professionalism by focusing on their understandings of educational work. The idea standing at the core of this research is that exploring the concept of professionalism from a ground-up perspective could lead to important reflections for a re-conceptualisation of professional development as a space for change directed from within institutions. The study is framed within a broadly sociological concern that inform the data analysis by contextualising the issue of early childhood professionalism in the contemporary socio-political arena. The research involves sixty teachers operating in state, municipal and private pre-school institutions located in Bologna province that took part to focus groups and interviews. The empirical materials, consisting of oral and written statements, are interpreted through phenomenographical analysis that gives account of how features of professionalism vary across the different institutional settings in which they are played out. This thesis, written in English and informed by an European research background, offers a contribution to the furthering of systemic approaches to the investigation of early childhood education professionalism in the context of the national and international academic debate.

Lexis paidike. L'infanzia in Origene

La tesi considera la trattazione del tema dell’infanzia nell’opera di Origene di Alessandria attraverso l’analisi dei testi trasmessi nell’originale greco e delle traduzioni latine di Rufino e Gerolamo. Il motivo dell’infanzia è considerato nei suoi molteplici significati, a più livelli: esegetico, antropologico, filosofico, teologico. La ricerca non si limita dunque ad un’analisi di taglio storico, ma ambisce a definire la concezione e la considerazione della prima età dal punto di vista di Origene e nel contesto più ampio della letteratura coeva. Attraverso una lettura estensiva del corpus dell’Alessandrino sono stati isolati tutti i passi che si riferiscono all’infanzia a livello letterale e metaforico. Ne emerge una trattazione complessa del tema: il bambino è per Origene, in linea con le contemporanee dottrine filosofiche, un essere eminentemente irrazionale. Il pieno sviluppo della facoltà razionale si colloca al termine di questa prima fase dell’esistenza. L’irrazionalità infantile previene nei più piccoli l’insorgere delle passioni. A questa dottrina, di matrice stoica, si ricollegano alcuni sviluppi di grande rilievo: la non-imputabilità dei minori ed il legame tra razionalità e responsabilità individuale; la riflessione sulla sofferenza dei bambini e la ricerca di una sua causa, che non intacchi il principio della giustizia divina; l’ipotesi della preesistenza delle anime. Sul piano teologico la ricerca si focalizza sulle nozioni di paternità e filiazione e sul tema, centrale nell’orizzonte origeniano, della pedagogia. Origene concepisce la pedagogia umana, sul modello di quella divina, come una rete dinamica di relazioni che ricalca i rapporti parentali. A fianco di questi ambiti d’interesse principali l’analisi considera aspetti ulteriori: risalto è concesso, in particolare, all’elemento biografico ed all’aspetto linguistico e letterario della prosa origeniana, quest'ultimo spesso trascurato dalla critica. Lo studio mostra inoltre la vitalità di alcuni modelli esegetici origeniani nella tradizione successiva.