Optimization of the BDX experiment for Light Dark Matter searches at JLab

The Light Dark Matter (LDM) hypothesis postulates the existence of a new class of sub-GeV particles, neutral under Standard Model (SM) interactions. In its simplest form, LDM consists of particles $\chi$ with masses below 1 GeV/c$^2$, interacting with SM particles via a new force mediated by a light, spin-1 boson $A'$, commonly referred to as ``Dark Photon". This framework envisions a distinct ``Dark Sector" with its own particles and interactions, offering a theoretically well motivated explanation for Dark Matter, consistent with astrophysical observations and a thermal production mechanism. The \textit{Beam Dump eXperiment} (BDX) is an approved experiment at Jefferson Lab designed to search for Light Dark Matter. BDX will utilize an 11 GeV electron beam impinging on a thick target to produce a forward-boosted secondary beam of Light Dark Matter particles, which will then be detected by a dedicated downstream detector. Approved in 2018, BDX is expected to be commissioned in 2026 and run in 2027-2029. My thesis focuses on the preparatory work to deploy the BDX experiment. The detector design has been optimized to balance practicality with enhanced Light Dark Matter detection capabilities. Extensive characterization of detector components has been performed to ensure a precise understanding of detector response. A custom Monte Carlo framework has been developed to simulate Light Dark Matter signal and explore various theoretical models of interest. Additionally, a comprehensive data analysis framework has been developed to maximize the experiment sensitivity to Light Dark Matter, with optimizations based on expected detector performance. The ultimate goal of this thesis is to optimize BDX as a flagship experiment in Light Dark Matter searches, enabling it to probe different Dark Matter models

Ideas, Attitudes and Beliefs about Language in Italy from the Thirteenth to the Fifteenth Century

Peter Burke has described the early modern period in Europe as the age of the ‘discovery of language’. The aim of my dissertation is to trace the linguistic and cultural phenomena which prepared the way for this discovery by studying how ideas, attitudes and beliefs about language were formed and developed in Italy from the thirteenth to the fifteenth century. In particular, I analyse the contemporary perception of the shifting relationship between Latin and the vernaculars in light of two highly significant events in the social history of language: on the one hand, the collapse of the medieval language system of functional compartmentalization of Latin and vernaculars, which is usually referred to as diglossia; on the other hand, the process of the formation of national languages known as standardization. I examine the concept of ‘historical language’ and construct a theoretical framework to analyse how it was formed and developed within communities of speakers. From this perspective, I discuss how specific varieties of the vernacular came to acquire recognition; and I interpret in sociological and historical terms the progressive emancipation of the vernaculars from Latin and their acquisition of autonomous existence in the minds of speakers. Finally, I advance an interpretation of the language ideas and choices of Italian humanists and the role they played in changing the image of Latin in early modern Italy and making it a prototype of European standardized national languages

A case report of femoral head fracture with osteochondral lesion treated by osteosynthesis and biomimetic scaffold: 2-year clinical and radiological follow-up

The aim of the present study was to present clinical and radiological outcome of a hip fracture-dislocation of the femoral head treated with biomimetic osteochondral scaffold. An 18-year-old male was admitted to the hospital after a motorcycle-accident. He presented with an obturator hip dislocation with a type IVA femoral head fracture according to Brumback classification system. The patient underwent surgery 5 days after accident. The largest osteochondral fragment was reduced and stabilized with 2 screws, and the small fragments were removed. The residual osteochondral area was replaced by a biomimetic nanostructured osteochondral scaffold. At 1-year follow-up the patient did not complain of hip pain and could walk without limp. At 2-year follow-up he was able to run with no pain and he returned to practice sports. Repeated radiographs and magnetic resonance imaging studies of the hip showed no signs of osteoarthritis or evidence of avascular necrosis. A hyaline-like signal on the surface of the scaffold was observed with restoration of the articular surface and progressive decrease of the subchondral edema. The results of the present study showed that the biomimetic nanostructured osteochondral scaffold could be a promising and safe option for the treatment of traumatic osteochondral lesions of the femoral head. Study Design: Case report

Enigmatic Ladies of the Rings: How Cohesin Dysfunction Affects Myeloid Neoplasms Insurgence

The genes of the cohesin complex exert different functions, ranging from the adhesion of sister chromatids during the cell cycle, DNA repair, gene expression and chromatin architecture remodeling. In recent years, the improvement of DNA sequencing technologies allows the identification of cohesin mutations in different tumors such as acute myeloid leukemia (AML), acute megakaryoblastic leukemia (AMKL), and myelodysplastic syndromes (MDS). However, the role of cohesin dysfunction in cancer insurgence remains elusive. In this regard, cells harboring cohesin mutations do not show any increase in aneuploidy that might explain their oncogenic activity, nor cohesin mutations are sufficient to induce myeloid neoplasms as they have to co-occur with other causative mutations such as NPM1, FLT3-ITD, and DNMT3A. Several works, also using animal models for cohesin haploinsufficiency, correlate cohesin activity with dysregulated expression of genes involved in myeloid development and differentiation. These evidences support the involvement of cohesin mutations in myeloid neoplasms

Terrestrial Remote Sensing techniques to complement conventional geomechanical surveys for the assessment of landslide hazard: The San Leo case study (Italy)

The San Leo village, located near to Rimini (northern Italy), was built in the medieval period on the top of a calcarenite and sandstone plateau, affected by lateral spreading associated with secondary rock falls and topples. In fact, a number of landslides endangered the historical town since centuries. In order to describe the structural features driving these slope instability phenomena, a complete Terrestrial Laser Scanner (TLS) survey all around the San Leo cliff was performed. Moreover, Close-Range Photogrammetric (CRP) surveys and conventional geomechanical surveys on scanlines have been carried out. The 3D geometry of the cliffs was extracted and critical areas have been investigated in detail using dense Digital Surface Models (DSMs) obtained from CRP or TLS. The results were used to define the structural features of the plateau, to recognize more fractured areas, and to perform kinematic analyses, in order to assess the joint sets predisposing to slope instability at the cliff scale. The creation of a 3D model was also fundamental for the implementation of the geological model to be used in numerical modelling for hydrogeological characterization and slope stability analyses

Targets for cancer therapy in childhood sarcomas

Development of chemotherapeutic treatment modalities resulted in a dramatic increase in the survival of children with many types of cancer. Still, in case of some pediatric cancer entities including rhabdomyosarcoma, osteosarcoma and Ewing's sarcoma, survival of patients remains dismal and novel treatment approaches are urgently needed. Therefore, based on the concept of targeted therapy, numerous potential targets for the treatment of these cancers have been evaluated pre-clinically or in some cases even clinically during the last decade. This review gives an overview over many different potential therapeutic targets for treatment of these childhood sarcomas, including receptor tyrosine kinases, intracellular signaling molecules, cell cycle and apoptosis regulators, proteasome, hsp90, histone deacetylases, angiogenesis regulators and sarcoma specific fusion proteins. The large number of potential therapeutic targets suggests that improved comparability of pre-clinical models might be necessary to prioritize the most effective ones for future clinical trials

Secondary Beams at High-Intensity Electron Accelerator Facilities

The interaction of a high-current $O$(100~\textmu A), medium energy $O$(10\,GeV) electron beam with a thick target $O$(1m) produces an overwhelming shower of standard matter particles in addition to hypothetical Light Dark Matter particles. While most of the radiation (gamma, electron/positron, and neutron) is contained in the thick target, deep penetrating particles (muons, neutrinos, and light dark matter particles) propagate over a long distance, producing high-intense secondary beams. Using sophisticated Monte Carlo simulations based on FLUKA and GEANT4, we explored the characteristics of secondary muons and neutrinos and (hypothetical) dark scalar particles produced by the interaction of Jefferson Lab 11 GeV intense electron beam with the experimental Hall-A beam dump. Considering the possible beam energy upgrade, this study was repeated for a 20 GeV CEBAF beam

TCR repertoire sequencing identifies synovial Treg cell clonotypes in the bloodstream during active inflammation in human arthritis

Objectives The imbalance between effector and regulatory T (Treg) cells is crucial in the pathogenesis of autoimmune arthritis. Immune responses are often investigated in the blood because of its accessibility, but circulating lymphocytes are not representative of those found in inflamed tissues. This disconnect hinders our understanding of the mechanisms underlying disease. Our goal was to identify Treg cells implicated in autoimmunity at the inflamed joints, and also readily detectable in the blood upon recirculation. Methods We compared Treg cells of patients with juvenile idiopathic arthritis responding or not to therapy by using: (i) T cell receptor (TCR) sequencing, to identify clonotypes shared between blood and synovial fluid; (ii) FOXP3 Treg cell-specific demethylated region DNA methylation assays, to investigate their stability and (iii) flow cytometry and suppression assays to probe their tolerogenic functions. Results We found a subset of synovial Treg cells that recirculated into the bloodstream of patients with juvenile idiopathic and adult rheumatoid arthritis. These inflammation-associated (ia)Treg cells, but not other blood Treg cells, expanded during active disease and proliferated in response to their cognate antigens. Despite the typical inflammatory-skewed balance of immune mechanisms in arthritis, iaTreg cells were stably committed to the regulatory lineage and fully suppressive. A fraction of iaTreg clonotypes were in common with pathogenic effector T cells. Conclusions Using an innovative antigen-agnostic approach, we uncovered a population of bona fide synovial Treg cells readily accessible from the blood and selectively expanding during active disease, paving the way to non-invasive diagnostics and better understanding of the pathogenesis of autoimmunity

SEMA6A drives GnRH neuron-dependent puberty onset by tuning median eminence vascular permeability

Innervation of the hypothalamic median eminence by Gonadotropin-Releasing Hormone (GnRH) neurons is vital to ensure puberty onset and successful reproduction. However, the molecular and cellular mechanisms underlying median eminence development and pubertal timing are incompletely understood. Here we show that Semaphorin-6A is strongly expressed by median eminence-resident oligodendrocytes positioned adjacent to GnRH neuron projections and fenestrated capillaries, and that Semaphorin-6A is required for GnRH neuron innervation and puberty onset. In vitro and in vivo experiments reveal an unexpected function for Semaphorin-6A, via its receptor Plexin-A2, in the control of median eminence vascular permeability to maintain neuroendocrine homeostasis. To support the significance of these findings in humans, we identify patients with delayed puberty carrying a novel pathogenic variant of SEMA6A. In all, our data reveal a role for Semaphorin-6A in regulating GnRH neuron patterning by tuning the median eminence vascular barrier and thereby controlling puberty onset