Studies on the Hippo Pathway: new insights about a multifaceted signalling

The Hippo pathway is a well-known master regulator of cell growth and proliferation. Many studies have shed light on the centrality of Hippo functions, as this signalling is able to respond to different stimuli and translate them into distinct transcriptional outputs. Therefore, it is clearly implicated in a number of important processes, which alteration has consequences on the correct specification of the single cell, as well as the whole tissue. Even if the core of the signalling has been extensively characterized, it remains unclear which are the “co-workers” that permit the Hippo pathway to answer to so many different stimuli and act as a coordinator of the growth/differentiation balance. Taking advantage of the Drosophila model, which has witnessed most of the discoveries on this signalling pathway, this thesis aims to add some new knowledge about the Hippo pathway molecular mechanisms in different contexts, from development to disease. In the first part I studied the dynamics of the Hippo core kinase protein Warts in the development of the pupal eye. I have found out a critical time point in which the expression and the localization of Warts change suddenly, suggesting the intervention of upstream regulators modulating its activity in an extremely narrow time window. The second goal was investigating the role of the Hippo pathway in the neurodegenerative Gaucher disease. Indeed, I have produced some preliminary results which demonstrate a growth deficit associated with a massive reduction of some Yki targets, supporting a Hyper-Hippo condition underlying this neuropathic syndrome. Finally, I have evaluated the transcription factor Orthodenticle as a co-factor of Yorkie in driving tissue overgrowth, and my findings support a model of interaction of these two molecules based on Yki conformational changes. Altogether, my results lay the foundation for new important studies on the molecular mechanisms ruling Hippo pathway activity.

The ontogeny of bipedalism: insights from the study of talar growth

The development of bipedal locomotion was gradual during evolution, and with the increase in discoveries of fossils and, in particular, in discoveries of pedal bones, the attention to this problematic has grown in the last decades. Moreover, the discoveries of juveniles fossil foot bones has led the attention to the evolution and the development of bipedal locomotion. The study of the development of human gait in children may help in shedding light to the development of human locomotion. The human talus plays a pivotal role, linking the leg to the foot and receiving and distributing the weight, while permitting a wide range of foot movements. It is also present at birth, and this makes a perfect bone to study to disentangle how the bone structure acts to cope with the changes in locomotion and body weight. Here, I analyze the external and internal morphology of the human talus from the perinatal period to adolescence, to investigate how the different phases of the acquisition of bipedal gait affect talar morphology, and how the bone copes with the weight gain during growth. Results show that the talar internal and external morphologies change in line with the different activities and loading of the foot. Initially, at around birth, the talus has a very globular and immature external shape, with a very dense trabecular architecture, composed of thin, numerous, and densely packed trabeculae, with a rather isotropic structure. External and internal morphologies change in relation to the different loading patterns which follow during growth, showing a more specialized structure, both in the external and internal morphology, linked to the maturation of bipedal locomotion, until the adult-like pattern is reached, during adolescence.

Monitoring and Prediction of Thermal Emergencies in High Performance Computing Systems

Modern scientific discoveries are driven by an unsatisfiable demand for computational resources. High-Performance Computing (HPC) systems are an aggregation of computing power to deliver considerably higher performance than one typical desktop computer can provide, to solve large problems in science, engineering, or business. An HPC room in the datacenter is a complex controlled environment that hosts thousands of computing nodes that consume electrical power in the range of megawatts, which gets completely transformed into heat. Although a datacenter contains sophisticated cooling systems, our studies indicate quantitative evidence of thermal bottlenecks in real-life production workload, showing the presence of significant spatial and temporal thermal and power heterogeneity. Therefore minor thermal issues/anomalies can potentially start a chain of events that leads to an unbalance between the amount of heat generated by the computing nodes and the heat removed by the cooling system originating thermal hazards. Although thermal anomalies are rare events, anomaly detection/prediction in time is vital to avoid IT and facility equipment damage and outage of the datacenter, with severe societal and business losses. For this reason, automated approaches to detect thermal anomalies in datacenters have considerable potential. This thesis analyzed and characterized the power and thermal characteristics of a Tier0 datacenter (CINECA) during production and under abnormal thermal conditions. Then, a Deep Learning (DL)-powered thermal hazard prediction framework is proposed. The proposed models are validated against real thermal hazard events reported for the studied HPC cluster while in production. This thesis is the first empirical study of thermal anomaly detection and prediction techniques of a real large-scale HPC system to the best of my knowledge. For this thesis, I used a large-scale dataset, monitoring data of tens of thousands of sensors for around 24 months with a data collection rate of around 20 seconds.

La ricerca archeologica e il regime dei ritrovamenti e delle scoperte nel sottosuolo e nei fondali marini. La disciplina del Codice tra attuazione e prospettive di riforma anche alla luce di un'analisi comparativa con l'esperienza francese e spagnola.

Il lavoro è volto all’approfondimento, anche in chiave comparatistica, della vigente normativa riguardante la tutela e la valorizzazione dei beni archeologici. Nell’ambito della disciplina predisposta nell’ordinamento italiano si sono prese le mosse dal regime delle scoperte e dei ritrovamenti, per passare successivamente all’approfondimento della tutela approntata nella legislazione nazionale anche con riferimento alle limitazioni alla libera disponibilità e circolazione. Una particolare attenzione è stata dedicata alla tutela del territorio in cui i beni archeologici sono inseriti e quindi alla tutela indiretta, ai vincoli ope legis e alla pianificazione paesaggistica, mentre una specifica trattazione ha riguardato il regime dell’archeologia preventiva e la valorizzazione e fruizione di aree e parchi archeologici nel reciproco interfacciarsi delle legislazioni regionali e delle linee guida emanate con il d.m. MiBAC 18 aprile 2012. Un’indagine articolata ha avuto per oggetto la tutela del patrimonio archeologico subacqueo e in particolare la Convenzione dell’UNESCO adottata a Parigi nel 2001, nonché la tutela sovranazionale dei beni culturali, con riferimento alla disciplina dell’Unione europea e a quella della Convenzione europea per la protezione del patrimonio archeologico del 16 gennaio 1992 e della Convenzione UNIDROIT del 24 giugno 1995 sui beni culturali rubati o esportati illegalmente. Hanno infine fatto seguito due specifiche indagini sulla tutela del patrimonio archeologico in Spagna e in Francia. Quanto alla prima si è esaminato l’attuale quadro costituzionale in cui si inserisce la tutela del patrimonio culturale con particolare attenzione alle disposizioni della Ley 16/1985 del 25 giugno 1985 e alla legislazione delle Comunidades autónomas. Per quanto riguarda la seconda una particolare attenzione è stata dedicata alla Legge 27 settembre 1941 che ha introdotto in Francia la prima disciplina organica relativa agli scavi e ai ritrovamenti archeologici. Nel quadro normativo vigente un’analisi particolareggiata è stata dedicata al Code du Patrimoine, il cui quinto libro è interamente dedicato all’archeologia.

Non-thermal phenomena in galaxy clusters: the LOFAR revolution

Turbulence introduced into the intra-cluster medium (ICM) through cluster merger events transfers energy to non-thermal components (relativistic particles and magnetic fields) and can trigger the formation of diffuse synchrotron radio sources. Owing to their steep synchrotron spectral index, such diffuse sources can be better studied at low radio frequencies. In this respect, the LOw Frequency ARray (LOFAR) is revolutionizing our knowledge thanks to its unprecedented resolution and sensitivity below 200 MHz. In this Thesis we focus on the study of radio halos (RHs) by using LOFAR data. In the first part of this work we analyzed the largest-ever sample of galaxy clusters observed at radio frequencies. This includes 309 Planck clusters from the Second Data Release of the LOFAR Two Metre Sky Survey (LoTSS-DR2), which span previously unexplored ranges of mass and redshift. We detected 83 RHs, half of which being new discoveries. In 140 clusters we lack a detected RH; for this sub-sample we developed new techniques to derive upper limits to their radio powers. By comparing detections and upper limits, we carried out the first statistical analysis of populations of clusters observed at low frequencies and tested theoretical formation models. In the second part of this Thesis we focused on ultra-steep spectrum radio halos. These sources are almost undetected at GHz frequencies, but are thought to be common at low frequencies. We presented LOFAR observations of two interesting clusters hosting ultra-steep spectrum radio halos. With complementary radio and X-ray observations we constrained the properties and origin of these targets.

Real-time anomaly detection of gamma-ray bursts for the Cherenkov Telescope Array using deep learning

The Cherenkov Telescope Array (CTA) will be the next-generation ground-based observatory to study the universe in the very-high-energy domain. The observatory will rely on a Science Alert Generation (SAG) system to analyze the real-time data from the telescopes and generate science alerts. The SAG system will play a crucial role in the search and follow-up of transients from external alerts, enabling multi-wavelength and multi-messenger collaborations. It will maximize the potential for the detection of the rarest phenomena, such as gamma-ray bursts (GRBs), which are the science case for this study. This study presents an anomaly detection method based on deep learning for detecting gamma-ray burst events in real-time. The performance of the proposed method is evaluated and compared against the Li&Ma standard technique in two use cases of serendipitous discoveries and follow-up observations, using short exposure times. The method shows promising results in detecting GRBs and is flexible enough to allow real-time search for transient events on multiple time scales. The method does not assume background nor source models and doe not require a minimum number of photon counts to perform analysis, making it well-suited for real-time analysis. Future improvements involve further tests, relaxing some of the assumptions made in this study as well as post-trials correction of the detection significance. Moreover, the ability to detect other transient classes in different scenarios must be investigated for completeness. The system can be integrated within the SAG system of CTA and deployed on the onsite computing clusters. This would provide valuable insights into the method's performance in a real-world setting and be another valuable tool for discovering new transient events in real-time. Overall, this study makes a significant contribution to the field of astrophysics by demonstrating the effectiveness of deep learning-based anomaly detection techniques for real-time source detection in gamma-ray astronomy.