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

Water and sediments geochemistry and elemental fluxes on a Large Dam: case study of Ridracoli reservoir.

Since the study of Large Dam Reservoirs is of worldwide interest, in this PhD project we investigated the Ridracoli reservoir, one of the main water supply in Emilia-Romagna (north-eastern Italy). This work aims to characterize waters and sediments to better understand their composition, interactions and any process that occurs, for a better geochemical and environmental knowledge of the area. Physical and chemical analyses on the water column have shown an alternation of stratification and mixing of water in the reservoir’s water body due to seasonal variations in temperature and density. In particular, it was observed the establishment, in late summer, of anoxic conditions at the bottom, which in turn affects the concentration and mobility of some elements of concern (e.g. Fe and Mn) for the water quality. Sediments within the reservoir and from surrounding areas were analysed for organic matter, total inorganic composition and grain size, assessing the inter-element relationship, grain size, geological background and damming influences on their chemistry, through descriptive statistics, Principal Component Analysis and Cluster Analysis. The reservoir’s area was also investigated by pseudo total composition (Aqua Regia digestion), degree of elements extractability, and enrichment factors, then analysed and compared to limits by law and literature. Sediment cores, interstitial waters, and benthic chamber data from the bottom were of great interest due to organic matter degradation, early diagenesis, mineral formation at water-sediment interface and observed flows. Finally, leaching test and extraction procedures, of environmental interest, showed peculiar partitioning, both regarding spatial and in-depth distribution, and the absence of pollution. Collectively, our results are useful for the comprehension of processes that occur in water and sediments of Ridracoli reservoir, providing important knowledges on the site that could be relevant for the management of the resource and the planning of future interventions.

Anthropogenic and climatic controls on surface water across the contiguous United States

Anthropogenic activities and climatic processes heavily influence surface water resources by causing their progressive depletion, which in turn affects both societies and the environment. Therefore, there is an urgent need to understand the contribution of human and climatic dynamics on the variation of surface water availability. Here, this investigation is performed on the contiguous United States (CONUS) using remotely-sensed data. Three anthropogenic (i.e., urban area, population, and irrigation) and two climatic factors (i.e., precipitation and temperature) were selected as potential drivers of changes in surface water extent and the overlap between the increase or decrease in these drivers and the variation of surface water was examined. Most of the river basins experienced a surface water gain due to precipitation increase (eastern CONUS), and a reduction of irrigated land (western CONUS). River basins of the arid southwestern region and some river basins of the northeastern area encountered a surface water loss, essentially induced by population growth, along with a precipitation deficit and a general expansion of irrigated land. To further inspect the role of population growth and urbanization on surface water loss, the spatial interaction between human settlements and surface water depletion was examined by evaluating the frequency of surface water loss as a function of distance from urban areas. The decline of the observed frequency was successfully reproduced with an exponential distance-decay model, proving that surface water losses are more concentrated in the proximity of cities. Climatic conditions influenced this pattern, with more widely distributed losses in arid regions compared to temperate and continental areas. The results presented in this Thesis provide an improved understanding of the effects of anthropogenic and climatic dynamics on surface water availability, which could be integrated in the definition of sustainable strategies for urbanization, water management, and surface water restoration.

Development of thermochemiluminescence-based sensitive probes: synthesis, optimization, and characterization of c2- and c7-substituted acridine-containing 1,2-dioxetanes

After initial efforts in the late 1980s, the interest in thermochemiluminescence (TCL) as an effective detection technique has gradually faded due to some drawbacks, such as the high temperatures required to trigger the light emission and the relatively low intensities, which determined a poor sensitivity. Recent advances made with the adoption of variably functionalized 1,2-dioxetanes as innovative luminophores, have proved to be a promising approach for the development of reagentless and ultrasensitive detection methods exploitable in biosensors by using TCL compounds as labels, as either single molecules or included in modified nanoparticles. In this PhD Thesis, a novel class of N-substituted acridine-containing 1,2-dioxetanes was designed, synthesized, and characterized as universal TCL probes endowed with optimal emission-triggering temperatures and higher detectability particularly useful in bioanalytical assays. The different decorations introduced by the insertion of both electron donating (EDGs) and electron withdrawing groups (EWGs) at the 2- and 7-positions of acridine fluorophore was found to profoundly affect the photophysical properties and the activation parameters of the final 1,2-dioxetane products. Challenges in the synthesis of 1,2-dioxetanes were tackled with the recourse to continuous flow photochemistry to achieve the target parent compound in high yields, short reaction time, and easy scalability. Computational studies were also carried out to predict the olefins reactivity in the crucial photooxygenation reaction as well as the final products stability. The preliminary application of TCL prototype molecule has been performed in HaCaT cell lines showing the ability of these molecules to be detected in real biological samples and cell-based assays. Finally, attempts on the characterization of 1,2-dioxetanes in different environments (solid state, optical glue and nanosystems) and the development of bioconjugated TCL probes will be also presented and discussed.

A hydrodynamical view on the mass accretion onto massive halos

This Thesis presents the results of my work on how galaxy clusters form by the accretion of sub-clumps and diffuse materials, and how the accreted energy is distributed in the X-ray emitting plasma. Indeed, on scales larger than tens of millions of light years, the Universe is self-organised by gravity into a spiderweb, the Cosmic Web. Galaxy clusters are the knots of this Cosmic Web, but a strong definition of filaments (which link different knots) and their physical proprieties, is still uncertain. Even if this pattern was determined by studying the spatial distribution of galaxies in the optical band, recently, also in the X-rays probes of filamentary structures around galaxy clusters were obtained. Therefore, given these observational facilities, the galaxy clusters’ outskirts are the best candidate regions to detect filaments and study their physical characteristics. However, from X-rays observations, we have only a few detections of cosmic filaments to date. On the other hand, it is crucial to understand how the accreted energy is dissipated in the baryon content of galaxy clusters and groups. Indeed, it is well known that in the central region of galaxy clusters and groups, the baryon fraction increases with the halo mass. On the outer region, the lack of X-rays constraints influences our understanding of the evolution of baryons in the halos volume. The standard assumption of “closed-box” system, for which the baryon fraction should approach the cosmological ratio Omega_bar/Omega_m, for galaxy clusters and groups seems to be too strong, especially for less massive objects. Moreover, a complete redshift evolution of baryons in galaxy clusters and groups is still missing.

On the effect of confounding in linear regression models: an approach based on the theory of quadratic forms

The main topic of this thesis is confounding in linear regression models. It arises when a relationship between an observed process, the covariate, and an outcome process, the response, is influenced by an unmeasured process, the confounder, associated with both. Consequently, the estimators for the regression coefficients of the measured covariates might be severely biased, less efficient and characterized by misleading interpretations. Confounding is an issue when the primary target of the work is the estimation of the regression parameters. The central point of the dissertation is the evaluation of the sampling properties of parameter estimators. This work aims to extend the spatial confounding framework to general structured settings and to understand the behaviour of confounding as a function of the data generating process structure parameters in several scenarios focusing on the joint covariate-confounder structure. In line with the spatial statistics literature, our purpose is to quantify the sampling properties of the regression coefficient estimators and, in turn, to identify the most prominent quantities depending on the generative mechanism impacting confounding. Once the sampling properties of the estimator conditionally on the covariate process are derived as ratios of dependent quadratic forms in Gaussian random variables, we provide an analytic expression of the marginal sampling properties of the estimator using Carlson’s R function. Additionally, we propose a representative quantity for the magnitude of confounding as a proxy of the bias, its first-order Laplace approximation. To conclude, we work under several frameworks considering spatial and temporal data with specific assumptions regarding the covariance and cross-covariance functions used to generate the processes involved. This study allows us to claim that the variability of the confounder-covariate interaction and of the covariate plays the most relevant role in determining the principal marker of the magnitude of confounding.

New perspectives on A.I. in sentencing. Human decision-making between risk assessment tools and protection of humans rights.

The aim of this thesis is to investigate a field that until a few years ago was foreign to and distant from the penal system. The purpose of this undertaking is to account for the role that technology could plays in the Italian Criminal Law system. More specifically, this thesis attempts to scrutinize a very intricate phase of adjudication. After deciding on the type of an individual's liability, a judge must decide on the severity of the penalty. This type of decision implies a prognostic assessment that looks to the future. It is precisely in this field and in prognostic assessments that, as has already been anticipated in the United, instruments and processes are inserted in the pre-trial but also in the decision-making phase. In this contribution, we attempt to describe the current state of this field, trying, as a matter of method, to select the most relevant or most used tools. Using comparative and qualitative methods, the uses of some of these instruments in the supranational legal system are analyzed. Focusing attention on the Italian system, an attempt was made to investigate the nature of the element of an individual's ‘social dangerousness’ (pericolosità sociale) and capacity to commit offences, types of assessments that are fundamental in our system because they are part of various types of decisions, including the choice of the best sanctioning treatment. It was decided to turn our attention to this latter field because it is believed that the judge does not always have the time, the means and the ability to assess all the elements of a subject and identify the best 'individualizing' treatment in order to fully realize the function of Article 27, paragraph 3 of the Constitution.

Rethinking the block. The 1970s European discourses on the city and the IBA Berlin 1979-87

The dissertation explores the relationship between projects for urban blocks and the discourses on the city between the late 1960s and the 1980s, with a particular focus on the blocks of the Internationale Bauausstellung (IBA) Berlin 1979-87. The main research questions center on whether and how the block changed in connection with the emerging ideas of the city during this period and whether these changes had, in turn, effects on the whole city. Thus far, despite extensive research on the theories and the ideas of the city between the 1960s and 1980s, there is a lack of studies that interweave this research with insights into the block. To fill this gap, this dissertation examines how the block was thematized in the 1970s discourses on the city. It highlights projects for blocks designed between the late 1960s and the 70s in various European cities, particularly West Berlin. Then, it focuses on the blocks of the IBA Berlin 1979-87, examining them through theory, history, and drawings. The study of the examples reveals three distinctive aspects of all blocks considered in the dissertation: the overcoming of small private plots, the individualization of the buildings, and the accessibility of the courtyards from public streets. These aspects reflect the changing understandings of the city and of the urban spaces in the 1970s and 1980s, which resulted in new compositional logics of the block. When examined with critical distance, the blocks of the 1970s and 80s offer a lesson in architectural and urban composition which is still current. - The author has made every effort to contact the owners of the copyrights of the material in the dissertation. The author is available to the right holders with whom it was not possible to communicate as well as for any omissions or inaccuracies in quoting the sources.

Study of charge, spin, and structural orderings in quantum materials using nuclei and muons as local probes

Quantum Materials are many body systems displaying emergent phenomena caused by quantum collective behaviour, such as superconductivity, charge density wave, fractional hall effect, and exotic magnetism. Among quantum materials, two families have recently attracted attention: kagome metals and Kitaev materials. Kagome metals have a unique crystal structure made up of triangular lattice layers that are used to form the kagome layer. Due to superconductivity, magnetism, and charge ordering states such as the Charge Density Wave (CDW), unexpected physical phenomena such as the massive Anomalous Hall Effect (AHE) and possible Majorana fermions develop in these materials. Kitaev materials are a type of quantum material with a unique spin model named after Alexei Kitaev. They include fractional fluctuations of Majorana fermions and non-topological abelian anyons, both of which might be used in quantum computing. Furthermore, they provide a realistic framework for the development of quantum spin liquid (QSL), in which quantum fluctuations produce long-range entanglements between electronic states despite the lack of classical magnetic ordering. In my research, I performed several nuclear magnetic resonance (NMR), nuclear quadrupole resonance (NQR), and muon spin spectroscopy (µSR) experiments to explain and unravel novel phases of matter within these unusual families of materials. NMR has been found to be an excellent tool for studying these materials’ local electronic structures and magnetic properties. I could use NMR to determine, for the first time, the structure of a novel kagome superconductor, RbV3Sb5, below the CDW transition, and to highlight the role of chemical doping in the CDW phase of AV3Sb5 superconductors. µSR has been used to investigate the effect of doping on kagome material samples in order to study the presence and behaviour of an anomalous phase developing at low temperatures and possibly related to time-reversal symmetry breaking.

Comparison of different solutions for the hybridization of a motorcycle engine for Formula Student applications and evaluation of the effectiveness on the simulated lap time

Following the latest environmental concerns, the importance of minimising the detrimental effect of emissions of terrestrial vehicles has become a major goal for the whole automotive field. The key to achieve an emission-free long term future is the electrification of vehicle fleets; this huge step cannot be taken without intermediate technologies. In this context, hybrid vehicles are fundamental to reach this goal. Specifically, mild hybrid vehicles represent a trade-off between cost and emissions that could act now as a bridge towards electrification. Like the industry, also student engineering competitions are likely to take the same route: Combustion vehicles may well turn into hybrid vehicles. For this reason, a preliminary design overview is necessary to pinpoint the key performance indicators for the prototypes of the future.

Obesity And Inflammation And The Effect On The Hematopoietic System.

Bone marrow is organized in specialized microenvironments known as 'marrow niches'. These are important for the maintenance of stem cells and their hematopoietic progenitors whose homeostasis also depends on other cell types present in the tissue. Extrinsic factors, such as infection and inflammatory states, may affect this system by causing cytokine dysregulation (imbalance in cytokine production) and changes in cell proliferation and self-renewal rates, and may also induce changes in the metabolism and cell cycle. Known to relate to chronic inflammation, obesity is responsible for systemic changes that are best studied in the cardiovascular system. Little is known regarding the changes in the hematopoietic system induced by the inflammatory state carried by obesity or the cell and molecular mechanisms involved. The understanding of the biological behavior of hematopoietic stem cells under obesity-induced chronic inflammation could help elucidate the pathophysiological mechanisms involved in other inflammatory processes, such as neoplastic diseases and bone marrow failure syndromes.

[theoretical Construction In The Sociology Of Health: A Reflection On Its Trajectory].

The scope of this paper is to reflect on the theoretical construction in the constitution of the sociology of health, still called medical sociology in some countries. Two main ideas constitute the basis for this: interdisciplinarity and the degree of articulation in the fields of medicine and sociology. We sought to establish a dialogue with some dimensions - macro/micro, structure/action - that constitute the basis for understanding medicine/health in relation to the social/sociological dimension. The main aspects of these dimensions are initially presented. Straus' two medical sociologies and the theory/application impasses are then addressed, as well as the dilemmas of the sociology of medicine in the 1960s and 1970s. From these analyses the theoretical production before 1970 is placed as a counterpoint. Lastly, the sociology of health is seen in the general context of sociology, which underwent a fragmentation process from 1970 with effects in all subfields of the social sciences. This process involves a rethinking of the theoretical issues in a broadened spectrum of possibilities. The 1980s are highlighted when theoretical issues in the sociology of health are reinvigorated and the issue of interdisciplinarity is once again addressed.

[almost An Autobiography: A Study Of Social Scientists In Health Based On The Lattes Curriculum].

Among the various ways of adopting the biographical approach, we used the curriculum vitaes (CVs) of Brazilian researchers who work as social scientists in health as our research material. These CVs are part of the Lattes Platform of CNPq - the National Council for Scientific and Technological Development, which includes Research and Institutional Directories. We analyzed 238 CVs for this study. The CVs contain, among other things, the following information: professional qualifications, activities and projects, academic production, participation in panels for the evaluation of theses and dissertations, research centers and laboratories and a summarized autobiography. In this work there is a brief review of the importance of autobiography for the social sciences, emphasizing the CV as a form of autobiographical practice. We highlight some results, such as it being a group consisting predominantly of women, graduates in social sciences, anthropology, sociology or political science, with postgraduate degrees. The highest concentration of social scientists is located in Brazil's southern and southeastern regions. In some institutions the main activities of social scientists are as teachers and researchers with great thematic diversity in research.

Mechanisms Predisposing Penile Fracture And Long-term Outcomes On Erectile And Voiding Functions.

Purpose. To determine the mechanisms predisposing penile fracture as well as the rate of long-term penile deformity and erectile and voiding functions. Methods. All fractures were repaired on an emergency basis via subcoronal incision and absorbable suture with simultaneous repair of eventual urethral lesion. Patients' status before fracture and voiding and erectile functions at long term were assessed by periodic follow-up and phone call. Detailed history included cause, symptoms, and single-question self-report of erectile and voiding functions. Results. Among the 44 suspicious cases, 42 (95.4%) were confirmed, mean age was 34.5 years (range: 18-60), mean follow-up 59.3 months (range 9-155). Half presented the classical triad of audible crack, detumescence, and pain. Heterosexual intercourse was the most common cause (28 patients, 66.7%), followed by penile manipulation (6 patients, 14.3%), and homosexual intercourse (4 patients, 9.5%). Woman on top was the most common heterosexual position (n = 14, 50%), followed by doggy style (n = 8, 28.6%). Four patients (9.5%) maintained the cause unclear. Six (14.3%) patients had urethral injury and two (4.8%) had erectile dysfunction, treated by penile prosthesis and PDE-5i. No patient showed urethral fistula, voiding deterioration, penile nodule/curve or pain. Conclusions. Woman on top was the potentially riskiest sexual position (50%). Immediate surgical treatment warrants long-term very low morbidity.

The Burden Of Eclampsia: Results From A Multicenter Study On Surveillance Of Severe Maternal Morbidity In Brazil.

Maternal mortality (MM) is a core indicator of disparities in women's rights. The study of Near Miss cases is strategic to identifying the breakdowns in obstetrical care. In absolute numbers, both MM and occurrence of eclampsia are rare events. We aim to assess the obstetric care indicators and main predictors for severe maternal outcome from eclampsia (SMO: maternal death plus maternal near miss). Secondary analysis of a multicenter, cross-sectional study, including 27 centers from all geographic regions of Brazil, from 2009 to 2010. 426 cases of eclampsia were identified and classified according to the outcomes: SMO and non-SMO. We classified facilities as coming from low- and high-income regions and calculated the WHO's obstetric health indicators. SPSS and Stata softwares were used to calculate the prevalence ratios (PR) and respective 95% confidence interval (CI) to assess maternal characteristics, clinical and obstetrical history, and access to health services as predictors for SMO, subsequently correlating them with the corresponding perinatal outcomes, also applying multiple regression analysis (adjusted for cluster effect). Prevalence of and mortality indexes for eclampsia in higher and lower income regions were 0.2%/0.8% and 8.1%/22%, respectively. Difficulties in access to health care showed that ICU admission (adjPR 3.61; 95% CI 1.77-7.35) and inadequate monitoring (adjPR 2.31; 95% CI 1.48-3.59) were associated with SMO. Morbidity and mortality associated with eclampsia were high in Brazil, especially in lower income regions. Promoting quality maternal health care and improving the availability of obstetric emergency care are essential actions to relieve the burden of eclampsia.