Development and description of a novel inducible model of salivary gland inflammation in C57BL/6 mice characterised by tertiary lymphoid structures, autoimmunity and exocrine dysfunction

PhDThe accumulation of leukocytes in non-lymphoid tissues and their structural organization into tertiary lymphoid structures (TLS), a process known as ectopic lymphoid neogenesis (ELN), is observed in response to chronic inflammation and in the target organ of several autoimmune diseases. TLS strongly resemble secondary lymphoid organs with specialised high-endothelial venules (HEV), segregated B/T cell areas and presence of follicular dendritic cells (FDC) networks promoting in situ affinity maturation of the antibody response. TLS have been associated with a growing number of autoimmune conditions and usually their presence is prognostic for undesirable disease progression. In Sjögren’s syndrome (SS), an autoimmune disease affecting the salivary and lachrymal glands leading to exocrine dysfunction, TLS develop in the salivary glands (SG) of around one-third of the patients. The immunobiology of the SG and the pathogenesis of SS have been poorly clarified and to date a robust and reproducible inducible animal model of SS and TLS in the SG is still absent. In my PhD, I developed and validated a novel inducible model of ELN in murine SG that also reproduces several features of SS. The retrograde administration of a replication-deficient adenovirus (AdV) in the SGs of wild-type C57Bl/6 mice was able to induce within three weeks fully formed TLS that displayed B/T cell segregation, FDC networks, HEVs and were positive for markers of germinal centres. Moreover, the AdV-treated mice showed a significant reduction of salivary flow and in 75% of the cases development of anti-nuclear antibodies

Quantum-inspired Machine Learning on high-energy physics data

Tensor Networks, a numerical tool originally designed for simulating quantum many-body systems, have recently been applied to solve Machine Learning problems. Exploiting a tree tensor network, we apply a quantum-inspired machine learning technique to a very important and challenging big data problem in high energy physics: the analysis and classification of data produced by the Large Hadron Collider at CERN. In particular, we present how to effectively classify so-called b-jets, jets originating from b-quarks from proton-proton collisions in the LHCb experiment, and how to interpret the classification results. We exploit the Tensor Network approach to select important features and adapt the network geometry based on information acquired in the learning process. Finally, we show how to adapt the tree tensor network to achieve optimal precision or fast response in time without the need of repeating the learning process. These results pave the way to the implementation of high-frequency real-time applications, a key ingredient needed among others for current and future LHCb event classification able to trigger events at the tens of MHz scale.Comment: 13 pages, 4 figure

Quantum Machine Learning for bb-jet charge identification

Machine Learning algorithms have played an important role in hadronic jet classification problems. The large variety of models applied to Large Hadron Collider data has demonstrated that there is still room for improvement. In this context Quantum Machine Learning is a new and almost unexplored methodology, where the intrinsic properties of quantum computation could be used to exploit particles correlations for improving the jet classification performance. In this paper, we present a brand new approach to identify if a jet contains a hadron formed by a $b$ or $\bar{b}$ quark at the moment of production, based on a Variational Quantum Classifier applied to simulated data of the LHCb experiment. Quantum models are trained and evaluated using LHCb simulation. The jet identification performance is compared with a Deep Neural Network model to assess which method gives the better performance

The Comparative Exploration of the Ice Giant Planets with Twin Spacecraft: Unveiling the History of our Solar System

In the course of the selection of the scientific themes for the second and third L-class missions of the Cosmic Vision 2015-2025 program of the European Space Agency, the exploration of the ice giant planets Uranus and Neptune was defined "a timely milestone, fully appropriate for an L class mission". Among the proposed scientific themes, we presented the scientific case of exploring both planets and their satellites in the framework of a single L-class mission and proposed a mission scenario that could allow to achieve this result. In this work we present an updated and more complete discussion of the scientific rationale and of the mission concept for a comparative exploration of the ice giant planets Uranus and Neptune and of their satellite systems with twin spacecraft. The first goal of comparatively studying these two similar yet extremely different systems is to shed new light on the ancient past of the Solar System and on the processes that shaped its formation and evolution. This, in turn, would reveal whether the Solar System and the very diverse extrasolar systems discovered so far all share a common origin or if different environments and mechanisms were responsible for their formation. A space mission to the ice giants would also open up the possibility to use Uranus and Neptune as templates in the study of one of the most abundant type of extrasolar planets in the galaxy. Finally, such a mission would allow a detailed study of the interplanetary and gravitational environments at a range of distances from the Sun poorly covered by direct exploration, improving the constraints on the fundamental theories of gravitation and on the behaviour of the solar wind and the interplanetary magnetic field.Comment: 29 pages, 4 figures; accepted for publication on the special issue "The outer Solar System X" of the journal Planetary and Space Science. This article presents an updated and expanded discussion of the white paper "The ODINUS Mission Concept" (arXiv:1402.2472) submitted in response to the ESA call for ideas for the scientific themes of the future L2 and L3 space mission

ACE2 and TMPRSS2 Potential Involvement in Genetic Susceptibility to SARS-COV-2 in Cancer Patients

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused a global pandemic. One open question is whether genetics could influence the severity of symptoms. Considering the limited data on cancer patients, we analyzed public data repositories limited to investigate angiotensin-converting enzyme 2 (ACE2) and the transmembrane serine protease 2 (TMPRSS2) expressions and genetic variants to identify the basis of individual susceptibility to SARS-CoV-2. Gene expression and variant data were retrieved from Tissue Cancer Genome Atlas, Genotype-Tissue Expression, and gnomAD. Differences in gene expression were tested with Mann-Whitney U-test. Allele frequencies of germline variants were explored in different ethnicities, with a special focus on ACE2 variants located in the binding site to SARS-CoV-2 spike protein. The analysis of ACE2 and TMPRSS2 expressions in healthy tissues showed a higher expression in the age class 20 to 59 years (false discovery rate [FDR] < 0.0001) regardless of gender. ACE2 and TMPRSS2 were more expressed in tumors from males than females (both FDR < 0.0001) and, opposite to the regulation in tissues from healthy individuals, more expressed in elderly patients (FDR = 0.005; FDR < 0.0001, respectively). ACE2 and TMPRSS2 expressions were higher in cancers of elderly patients compared with healthy individuals (FDR < 0.0001). Variants were present at low frequency (range 0% to 3%) and among those with the highest frequency, the variant S19P belongs to the SARS-CoV-2 spike protein binding site and it was exclusively present in Africans with a frequency of 0.2%. The mechanisms of ACE2 and TMPRSS2 regulation could be targeted for preventive and therapeutic purposes in the whole population and especially in cancer patients. Further studies are needed to show a direct correlation of ACE2 and TMPRSS2 expressions in cancer patients and the incidence of COVID-19

IL-22 regulates lymphoid chemokine production and assembly of tertiary lymphoid organs

The series of events leading to tertiary lymphoid organ (TLO) formation in mucosal organs following tissue damage remain unclear. Using a virus-induced model of autoantibody formation in the salivary glands of adult mice, we demonstrate that IL-22 provides a mechanistic link between mucosal infection, B-cell recruitment, and humoral autoimmunity. IL-22 receptor engagement is necessary and sufficient to promote differential expression of chemokine (C-X-C motif) ligand 12 and chemokine (C-X-C motif) ligand 13 in epithelial and fibroblastic stromal cells that, in turn, is pivotal for B-cell recruitment and organization of the TLOs. Accordingly, genetic and therapeutic blockade of IL-22 impairs and reverses TLO formation and autoantibody production. Our work highlights a critical role for IL-22 in TLO-induced pathology and provides a rationale for the use of IL-22–blocking agents in B-cell–mediated autoimmune conditions

L’utilizzo del Lat Gel nell’anestesia locale delle ferite pediatriche in Pronto Soccorso

Sedation and analgesia are common strategies to manage acute procedural pain and anxiety in Emergency Department, but no standardized protocol in children is approved. Application of topical LATgel (Lidocaine 4%, Adrenaline 0,05%, Tetracaine 0,5%) on wounds before painful procedures seems to be as effective as intradermal infiltrations in reducing procedural pain. A review of 34 paediatric cases from Pavullo Hospital (MO, Italy) presenting with laceration requiring suture was conducted. Pain assessment was performed in triage and, after 30mins of LATgel application, from parents, children and doctors during the suture. LATgel administration improves children’s compliance, minimizing pain and related fear during procedures. Our findings are consistent with international literature

The glucose transporter 2 regulates CD8⁺ T cell function via environment sensing

T cell activation is associated with a profound and rapid metabolic response to meet increased energy demands for cell division, differentiation and development of effector function. Glucose uptake and engagement of the glycolytic pathway are major checkpoints for this event. Here we show that the low-affinity, concentration-dependent glucose transporter 2 (Glut2) regulates the development of CD8+ T cell effector responses in mice by promoting glucose uptake, glycolysis and glucose storage. Expression of Glut2 is modulated by environmental factors including glucose and oxygen availability and extracellular acidification. Glut2 is highly expressed by circulating, recently primed T cells, allowing efficient glucose uptake and storage. In glucose-deprived inflammatory environments, Glut2 becomes downregulated, thus preventing passive loss of intracellular glucose. Mechanistically, Glut2 expression is regulated by a combination of molecular interactions involving hypoxia-inducible factor-1 alpha, galectin-9 and stomatin. Finally, we show that human T cells also rely on this glucose transporter, thus providing a potential target for therapeutic immunomodulation

ISWI Regulates Higher-Order Chromatin Structure and Histone H1 Assembly In Vivo

Imitation SWI (ISWI) and other ATP-dependent chromatin-remodeling factors play key roles in transcription and other processes by altering the structure and positioning of nucleosomes. Recent studies have also implicated ISWI in the regulation of higher-order chromatin structure, but its role in this process remains poorly understood. To clarify the role of ISWI in vivo, we examined defects in chromosome structure and gene expression resulting from the loss of Iswi function in Drosophila. Consistent with a broad role in transcriptional regulation, the expression of a large number of genes is altered in Iswi mutant larvae. The expression of a dominant-negative form of ISWI leads to dramatic alterations in higher-order chromatin structure, including the apparent decondensation of both mitotic and polytene chromosomes. The loss of ISWI function does not cause obvious defects in nucleosome assembly, but results in a significant reduction in the level of histone H1 associated with chromatin in vivo. These findings suggest that ISWI plays a global role in chromatin compaction in vivo by promoting the association of the linker histone H1 with chromatin