A tuple space implementation for large-scale infrastructures

Coordinating activities in a distributed system is an open research topic. Several models have been proposed to achieve this purpose such as message passing, publish/subscribe, workflows or tuple spaces. We have focused on the latter model, trying to overcome some of its disadvantages. In particular we have applied spatial database techniques to tuple spaces in order to increase their performance when handling a large number of tuples. Moreover, we have studied how structured peer to peer approaches can be applied to better distribute tuples on large networks. Using some of these result, we have developed a tuple space implementation for the Globus Toolkit that can be used by Grid applications as a coordination service. The development of such a service has been quite challenging due to the limitations imposed by XML serialization that have heavily influenced its design. Nevertheless, we were able to complete its implementation and use it to implement two different types of test applications: a completely parallelizable one and a plasma simulation that is not completely parallelizable. Using this last application we have compared the performance of our service against MPI. Finally, we have developed and tested a simple workflow in order to show the versatility of our service.

MCAO for Extremely Large Telescopes: the cases of LBT and E-ELT

Several MCAO systems are under study to improve the angular resolution of the current and of the future generation large ground-based telescopes (diameters in the 8-40 m range). The subject of this PhD Thesis is embedded in this context. Two MCAO systems, in dierent realization phases, are addressed in this Thesis: NIRVANA, the 'double' MCAO system designed for one of the interferometric instruments of LBT, is in the integration and testing phase; MAORY, the future E-ELT MCAO module, is under preliminary study. These two systems takle the sky coverage problem in two dierent ways. The layer oriented approach of NIRVANA, coupled with multi-pyramids wavefront sensors, takes advantage of the optical co-addition of the signal coming from up to 12 NGS in a annular 2' to 6' technical FoV and up to 8 in the central 2' FoV. Summing the light coming from many natural sources permits to increase the limiting magnitude of the single NGS and to improve considerably the sky coverage. One of the two Wavefront Sensors for the mid- high altitude atmosphere analysis has been integrated and tested as a stand- alone unit in the laboratory at INAF-Osservatorio Astronomico di Bologna and afterwards delivered to the MPIA laboratories in Heidelberg, where was integrated and aligned to the post-focal optical relay of one LINC-NIRVANA arm. A number of tests were performed in order to characterize and optimize the system functionalities and performance. A report about this work is presented in Chapter 2. In the MAORY case, to ensure correction uniformity and sky coverage, the LGS-based approach is the current baseline. However, since the Sodium layer is approximately 10 km thick, the articial reference source looks elongated, especially when observed from the edge of a large aperture. On a 30-40 m class telescope, for instance, the maximum elongation varies between few arcsec and 10 arcsec, depending on the actual telescope diameter, on the Sodium layer properties and on the laser launcher position. The centroiding error in a Shack-Hartmann WFS increases proportionally to the elongation (in a photon noise dominated regime), strongly limiting the performance. To compensate for this effect a straightforward solution is to increase the laser power, i.e. to increase the number of detected photons per subaperture. The scope of Chapter 3 is twofold: an analysis of the performance of three dierent algorithms (Weighted Center of Gravity, Correlation and Quad-cell) for the instantaneous LGS image position measurement in presence of elongated spots and the determination of the required number of photons to achieve a certain average wavefront error over the telescope aperture. An alternative optical solution to the spot elongation problem is proposed in Section 3.4. Starting from the considerations presented in Chapter 3, a first order analysis of the LGS WFS for MAORY (number of subapertures, number of detected photons per subaperture, RON, focal plane sampling, subaperture FoV) is the subject of Chapter 4. An LGS WFS laboratory prototype was designed to reproduce the relevant aspects of an LGS SH WFS for the E-ELT and to evaluate the performance of different centroid algorithms in presence of elongated spots as investigated numerically and analytically in Chapter 3. This prototype permits to simulate realistic Sodium proles. A full testing plan for the prototype is set in Chapter 4.

Early Warning For Large Earthquakes: Observations, Models and Real-Time Data Analysis

This thesis is a collection of works focused on the topic of Earthquake Early Warning, with a special attention to large magnitude events. The topic is addressed from different points of view and the structure of the thesis reflects the variety of the aspects which have been analyzed. The first part is dedicated to the giant, 2011 Tohoku-Oki earthquake. The main features of the rupture process are first discussed. The earthquake is then used as a case study to test the feasibility Early Warning methodologies for very large events. Limitations of the standard approaches for large events arise in this chapter. The difficulties are related to the real-time magnitude estimate from the first few seconds of recorded signal. An evolutionary strategy for the real-time magnitude estimate is proposed and applied to the single Tohoku-Oki earthquake. In the second part of the thesis a larger number of earthquakes is analyzed, including small, moderate and large events. Starting from the measurement of two Early Warning parameters, the behavior of small and large earthquakes in the initial portion of recorded signals is investigated. The aim is to understand whether small and large earthquakes can be distinguished from the initial stage of their rupture process. A physical model and a plausible interpretation to justify the observations are proposed. The third part of the thesis is focused on practical, real-time approaches for the rapid identification of the potentially damaged zone during a seismic event. Two different approaches for the rapid prediction of the damage area are proposed and tested. The first one is a threshold-based method which uses traditional seismic data. Then an innovative approach using continuous, GPS data is explored. Both strategies improve the prediction of large scale effects of strong earthquakes.

Investigating the role of Copy Number Variants in Specific Language Impairment and identification of new candidate genes

Specific language impairment (SLI) is a complex neurodevelopmental disorder defined as an unexpected failure to develop normal language abilities for no obvious reason. Copy number variants (CNVs) are an important source of variation in the susceptibility to neuropsychiatric disorders. Therefore, a CNV study within SLI families was performed to investigate the role of structural variants in SLI. Among the identified CNVs, we focused on CNVs on chromosome 15q11-q13, recurrently observed in neuropsychiatric conditions, and a homozygous exonic microdeletion in ZNF277. Since this microdeletion falls within the AUTS1 locus, a region linked to autism spectrum disorders (ASD), we investigated a potential role of ZNF277 in SLI and ASD. Frequency data and expression analysis of the ZNF277 microdeletion suggested that this variant may contribute to the risk of language impairments in a complex manner, that is independent of the autism risk previously described in this region. Moreover, we identified an affected individual with a dihydropyrimidine dehydrogenase (DPD) deficiency, caused by compound heterozygosity of two deleterious variants in the gene DPYD. Since DPYD represents a good candidate gene for both SLI and ASD, we investigated its involvement in the susceptibility to these two disorders, focusing on the splicing variant rs3918290, the most common mutation in the DPD deficiency. We observed a higher frequency of rs3918290 in SLI cases (1.2%), compared to controls (~0.6%), while no difference was observed in a large ASD cohort. DPYD mutation screening in 4 SLI and 7 ASD families carrying the splicing variant identified six known missense changes and a novel variant in the promoter region. These data suggest that the combined effect of the mutations identified in affected individuals may lead to an altered DPD activity and that rare variants in DPYD might contribute to a minority of cases, in conjunction with other genetic or non-genetic factors.

Analysis of Copy Number Variants identifies new candidate genes for Autism Spectrum Disorder and Intellectual Disability

Autism spectrum disorder (ASD) and Intellectual Disability (ID) are complex neuropsychiatric disorders characterized by extensive clinical and genetic heterogeneity and with overlapping risk factors. The aim of my project was to further investigate the role of Copy Numbers Variants (CNVs), identified through genome-wide studies performed by the Autism Geome Project (AGP) and the CHERISH consortium in large cohorts of ASD and ID cases, respectively. Specifically, I focused on four rare genic CNVs, selected on the basis of their impact on interesting ASD/ID candidate genes: a) a compound heterozygous deletion involving CTNNA3, predicted to cause the lack of functional protein; b) a 15q13.3 duplication containing CHRNA7; c) a 2q31.1 microdeletion encompassing KLHL23, SSB and METTL5; d) Lastly, I investigated the putative imprinting regulation of the CADPS2 gene, disrupted by a maternal deletion in two siblings with ASD and ID. This study provides further evidence for the role of CTNNA3, CHRNA7, KLHL23 and CADPS2 as ASD and/or ID susceptibility genes, and highlights that rare genetic variation contributes to disease risk in different ways: some rare mutations, such as those impacting CTNNA3, act in a recessive mode of inheritance, while other CNVs, such as those occurring in the 15q13.3 region, are implicated in multiple developmental and/or neurological disorders possibly interacting with other susceptibility variants elsewhere in the genome. On the other hand, the discovery of a tissue-specific monoallelic expression for the CADPS2 gene, implicates the involvement of epigenetic regulatory mechanisms as risk factors conferring susceptibility to ASD/ID.

TiMMing: developing an innovative suite of bioinformatic tools to harmonize and track the origin of copy number alterations in the evolutive history of multiple myeloma

Multiple Myeloma (MM) is a hematologic cancer with heterogeneous and complex genomic landscape, where Copy Number Alterations (CNAs) play a key role in the disease's pathogenesis and prognosis. It is of biological and clinical interest to study the temporal occurrence of early alterations, as they play a disease "driver" function by deregulating key tumor pathways. This study presents an innovative bioinformatic tools suite created for harmonizing and tracing the origin of CNAs throughout the evolutionary history of MM. To this aim, large cohorts of newly-diagnosed MM (NDMM, N=1582) and Smoldering-MM (SMM, N=282) were aggregated. The tools developed in this study enable the harmonization of CNAs as obtained from different genomic platforms in such a way that a high statistical power can be obtained. By doing so, the high numerosity of those cohorts was harnessed for the identification of novel genes characterized as "driver" (NFKB2, NOTCH2, MAX, EVI5 and MYC-ME2-enhancer), and the generation of an innovative timing model, implemented with a statistical method to introduce confidence intervals in the CNAs-calls. By applying this model on both NDMM and SMM cohorts, it was possible to identify specific CNAs (1q(CKS1B)amp, 13q(RB1)del, 11q(CCND1)amp and 14q(MAX)del) and categorize them as "early"/ "driver" events. A high level of precision was guaranteed by the narrow confidence intervals in the timing estimates. These CNAs were proposed as critical MM alterations, which play a foundational role in the evolutionary history of both SMM and NDMM. Finally, a multivariate survival model was able to identify the independent genomic alterations with the greatest effect on patients’ survival, including RB1-del, CKS1B-amp, MYC-amp, NOTCH2-amp and TRAF3-del/mut. In conclusion, the alterations that were identified as both "early-drivers” and correlated with patients’ survival were proposed as biomarkers that, if included in wider survival models, could provide a better disease stratification and an improved prognosis definition.