Harnessing the power of Drosophila model to obtain new insights on MYC and ABCC1 cellular functions: from neuroblastoma to autism spectrum disorder

MYCN amplification is a genetic hallmark of the childhood tumour neuroblastoma. MYCN-MAX dimers activate the expression of genes promoting cell proliferation. Moreover, MYCN seems to transcriptionally repress cell differentiation even in absence of MAX. We adopted the Drosophila eye as model to investigate the effect of high MYC to MAX expression ratio on cells. We found that dMyc overexpression in eye cell precursors inhibits cell differentiation and induces the ectopic expression of Antennapedia (the wing Hox gene). The further increase of MYC/MAX ratio results in an eye-to-wing homeotic transformation. Notably, dMyc overexpression phenotype is suppressed by low levels of transcriptional co-repressors and MYCN associates to the promoter of Deformed (the eye Hox gene) in proximity to repressive sites. Hence, we envisage that, in presence of high MYC/MAX ratio, the “free MYC” might inhibit Deformed expression, leading in turn to the ectopic expression of Antennapedia. This suggests that MYCN might reinforce its oncogenic role by affecting the physiological homeotic program. Furthermore, poor neuroblastoma outcome associates with a high level of the MRP1 protein, encoded by the ABCC1 gene and known to promote drug efflux in cancer cells. Intriguingly, this correlation persists regardless of chemotherapy and ABCC1 overexpression enhances neuroblastoma cell motility. We found that Drosophila dMRP contributes to the adhesion between the dorsal and ventral epithelia of the wing by inhibiting the function of integrin receptors, well known regulators of cell adhesion and migration. Besides, integrins play a crucial role during synaptogenesis and ABCC1 locus is included in a copy number variable region of the human genome (16p13.11) involved in neuropsychiatric diseases. Interestingly, we found that the altered dMRP/MRP1 level affects nervous system development in Drosophila embryos. These preliminary findings point out novel ABCC1 functions possibly defining ABCC1 contribution to neuroblastoma and to the pathogenicity of 16p13.11 deletion/duplication

Development discourse in Romania: from Socialism to EU Membership

With their accession to the European Union, twelve new countries - Romania among them - (re)entered the international community of international donors. In the history of development aid this can be seen as a unique event: it is for the first time in history that such a large number of countries become international donors, with such short notice and in such a particular context that sees some scholars announcing the ‘death’ of development. But in spite of what might be claimed regarding the ‘end’ of the development era, development discourse seems to be rather vigorous and in good health: it is able to extert an undeniable force of attraction over the twelve countries that, in a matter of years, have already convinced themselves of its validity and adhered to its main tenets. This thesis collects evidence for improving our understanding of this process that sees the co-optation of twelve new countries to the dominant theory and practice of development cooperation. The evidence collected seems to show that one of the tools employed by the promoters of this co-optation process is that of constructing the ‘new’ Member States as ‘new’, inexpert donors that need to learn from the ‘old’ ones. By taking a case-study approach, this thesis gathers data that suggests that conceiving of the ‘twelve’ as ‘new’ donors is both historically inaccurate and value-ladden. On one hand, Romania’s case-study illustrates how in the (socialist) past at least one in the group of the twelve was particularly conversant in the discourse of international development. On the other hand, the process of co-optation, while being presented as a knowledgeproducing process, can also be seen as an ignorance-producing procedure: Romania, along with its fellow new Member States, takes the opportunity of ‘building its capacity’ and ‘raising its awareness’ of development cooperation along the line drawn by the European Union, but at the same time it seems to un-learn and ‘lower’ its awareness of development experience in the (socialist) past. This is one possible reading of this thesis. At a different level, this thesis can also be seen as an attempt to account of almost five decades of international development discourse in one specific country – Romania – in three different socio-political contexts: the socialist years (up to the year 1989), the ‘transition years’ (from 1989 to the pre-accession years) and the membership to the European Union. In this second reading, the thesis seeks to illustrate how – contrary to widespread beliefs – before 1989 Romania’s international development discourse was particularly vivid: in the most varied national and international settings President Ceausescu unfolded an extensive discursive activity on issues pertaining to international development; generous media coverage of affairs concerning the developing countries and their fight for development was the rule rather than the exception; the political leadership wanted the Romanians not only to be familiarized with (or ‘aware of’ to use current terminology) matters of underdevelopment, but also to prove a sense of solidarity with these countries, as well as a sense of pride for the relations of ‘mutual help’ that were being built with them; finally, international development was object of academic attention and the Romanian scholars were able not only to reflect on major developments, but could also formulate critical positions towards the practices of development aid. Very little remains of all this during the transition years, while in the present those who are engaged in matters pertaining to international development do so with a view of building Romania as an EU-compliant donor.

Finite element models of coseismic deformation due to the 2009 L'Aquila (Italy) and 2008 Wenchuan(China) earthquakes

The topic of my Ph.D. thesis is the finite element modeling of coseismic deformation imaged by DInSAR and GPS data. I developed a method to calculate synthetic Green functions with finite element models (FEMs) and then use linear inversion methods to determine the slip distribution on the fault plane. The method is applied to the 2009 L’Aquila Earthquake (Italy) and to the 2008 Wenchuan earthquake (China). I focus on the influence of rheological features of the earth's crust by implementing seismic tomographic data and the influence of topography by implementing Digital Elevation Models (DEM) layers on the FEMs. Results for the L’Aquila earthquake highlight the non-negligible influence of the medium structure: homogeneous and heterogeneous models show discrepancies up to 20% in the fault slip distribution values. Furthermore, in the heterogeneous models a new area of slip appears above the hypocenter. Regarding the 2008 Wenchuan earthquake, the very steep topographic relief of Longmen Shan Range is implemented in my FE model. A large number of DEM layers corresponding to East China is used to achieve the complete coverage of the FE model. My objective was to explore the influence of the topography on the retrieved coseismic slip distribution. The inversion results reveals significant differences between the flat and topographic model. Thus, the flat models frequently adopted are inappropriate to represent the earth surface topographic features and especially in the case of the 2008 Wenchuan earthquake.

Taste receptors in the gut: a chemosensitive mechanism from fish to human

The ingestion of a meal evokes a series of digestive processes, which consist of the essential functions of the digestive system: food transport, secretory activity, absorption of nutrients and the expulsion of undigested residues do not absorbed. The gastrointestinal chemosensitivity is characterized by cellular elements of the endocrine gastrointestinal mucosa and nerve fibers, in particular of vagal nature. A wide range of mediators endocrine and/or paracrine can be released from various endocrine cells in response to nutrients in the diet. These hormones, in addition to their direct activity, act through specific receptors activating some of the most important functions in the control of energy intake and energy homeostasis in the body. For integration of this complex system of control of gastrointestinal chemosensitivity, recent evidence demonstrates the presence of taste receptors (TR) belonging to the family of G proteins coupled receptor expressed in the mucosa of the gastrointestinal tract of different mammals and human. This thesis is divided into several research projects that have been conceived in order to clarify the relationship between TR and nutrients. To define this relationship I have used various scientific approaches, which have gone on to evaluate changes in signal molecules of TR, in particular of the α-transducin in the fasting state and after refeeding with standard diet in the gastrointestinal tract of the pig, the mapping of the same molecule signal in the gastrointestinal tract of fish (Dicentrarchus labrax), the signaling pathway of bitter TR in the STC-1 endocrine cell line and finally the involvement of bitter TR in particular of T2R38 in patients with an excessive caloric intake. The results showed how there is a close correlation between nutrients, TR and hormonal release and how they are useful both in taste perception but also likely to be involved in chronic diseases such as obesity.