Measuring Ultrafast Chemical Dynamics with New Light Sources

This thesis summarizes the results and challenges of a series of experiments in the field of atomic and molecular physics carried out employing innovative light sources such as X-ray free electron lasers, high harmonic generation sources and ultrafast mid-IR lasers. The key feature common to all of them is the ability to provide ultrashort light pulses with a pulse duration in the 1-100 fs range (1 fs = 10-15 s) which in principle allows the investigation atomic and molecular dynamics unfolding on such time scales. The experiments described in this thesis constitute the first steps in this direction and shed light on the new challenges and opportunities that arise naturally when highly innovative tools are employed. In the main technological chapters, which follow a brief description of the various light sources, a variety of experimental techniques will be described, such as velocity map imaging, electron Time-of-Flight spectroscopy, ion Time-of-Flight mass spectroscopy and covariance mapping. Among these velocity map imaging is the one which has been used more extensively. A VMI spectrometer for electrons with kinetic energies in the 0-200 eV range has been designed and tested for the Artemis Lab at Rutherford Appleton Laboratories. For the analysis of the output images two well established algorithms for Abel inversion have been implemented and compared. In the first experimental chapter one of the first applications of the new Artemis VMI spectrometer will be described. In the TRPEI (time-resolved photoelectron imaging) Artemis experimental campaign the radiation produced by the monochromatized HHG beamline was employed to study the photoelectron angular distribution of electrons ejected from valence and inner valence shells in a number of atomic and molecular samples. Each of the remaining experimental chapters will be devoted to an experiment carried out at the first Hard X-ray Free Electron Laser facility in the world: the Linac Coherent Light Source. In the chapter devoted to the ring opening of 1,3-cyclohexadiene (CHD) a complex molecular reaction, namely the conrotatory electrocyclic opening of CHD to form the linear isomer 1,3,5-hexatriene, is studied on a time scale of 1 ps by X-ray induced fragmentation. Double core hole creation is the subject of the following chapter where the process is investigated with covariance mapping. Finally X-ray induced molecular dynamic following core excitation of molecular oxygen is addressed in the last chapter

Preliminary results of the Italian neutron experimental station INES at ISIS: Archaeometric applications

The INES project was sponsored by the CNR Neutron Spectroscopy Advisory Committee, stressing the importance of realizing an Italian Neutron Experimental Station (INES) at the world most powerful pulsed neutron source (ISIS, Rutherford Appleton Laboratory, UK) and evidencing the strategic value that such a test station would assume in the field of applied sciences like, for example, chemistry, material science, Earth science, crystallography, and last, but not least, in the field of science applied to the study of cultural-heritage artifacts

Preliminary results of the Italian neutron experimental station INES at ISIS: Archaeometric applications

The INES project was sponsored by the CNR Neutron Spectroscopy Advisory Committee, stressing the importance of realizing an Italian Neutron Experimental Station (INES) at the world most powerful pulsed neutron source (ISIS, Rutherford Appleton Laboratory, UK) and evidencing the strategic value that such a test station would assume in the field of applied sciences like, for example, chemistry, material science, Earth science, crystallography, and last, but not least, in the field of science applied to the study of cultural-heritage artifacts

Measurement of power spectral density of broad-spectrum visible light with heterodyne near field scattering and its scalability to betatron radiation.

We exploit the speckle field generated by scattering from a colloidal suspension to access both spatial and temporal coherence properties of broadband radiation. By applying the Wiener-Khinchine theorem to the retrieved temporal coherence function, information about the emission spectrum of the source is obtained in good agreement with the results of a grating spectrometer. Experiments have been performed with visible light. We prove more generally that our approach can be considered as a tool for modeling a variety of cases. Here we discuss how to apply such diagnostics to broad-spectrum betatron radiation produced in the laser-driven wakefield accelerator under development at SPARC LAB facility in Frascati

Tau Modulates VGluT1 Expression

Abstract Tau displacement from microtubules is the first step in the onset of tauopathies and is followed by toxic protein aggregation. However, other non-canonical functions of Tau might have a role in these pathologies. Here, we demonstrate that a small amount of Tau localizes in the nuclear compartment and accumulates in both the soluble and chromatin-bound fractions. We show that favoring Tau nuclear translocation and accumulation, by Tau overexpression or detachment from MTs, increases the expression of VGluT1, a disease-relevant gene directly involved in glutamatergic synaptic transmission. Remarkably, the P301L mutation, related to frontotemporal dementia FTDP-17, impairs this mechanism leading to a loss of function. Altogether, our results provide the demonstration of a direct physiological role of Tau on gene expression. Alterations of this mechanism may be at the basis of the onset of neurodegeneration

Local discrimination of orbital angular momentum in entangled states

We address the use of a calcite crystal-based local detector to the discrimination of orbital angular momentum of quantum radiation produced by parametric down conversion. We demonstrate that a discrimination can be obtained exploiting the introduction of a fine and controlled spatial shift between two replicas of the state in the crystals. We believe that this technology could be used for future development of long-distance quantum communication techniques, where information encoding is based on orbital angular momentum

Clinical experience with combination BRAF/MEK inhibitors for melanoma with brain metastases: a real-life multicenter study

BRAF and MEK kinase inhibitors can be highly effective in treating BRAF-mutant melanomas, but their safety and activity in patients with active/symptomatic brain metastases are unclear. We sought to shed light on this open clinical question. We conducted a multicenter retrospective study on real-life patients with melanoma and active brain metastases treated with combination BRAF/MEK inhibitors. A total of 65 patients were included (38 men and 27 women; median age: 49 years). Of them, 53 patients received dabrafenib/trametinib, 10 received vemurafenib/cobimetinib, one received encorafenib/binimetinib, and one received vemurafenib/trametinib. We did not observe any unexpected treatment-related safety signals in our cohort. Overall, 17 patients continued on therapy through the cutoff date. After initiation of therapy, steroid dose could be decreased in 22 of 33 patients (11 tapered off entirely), anticonvulsants were stopped in four of 21, and narcotics were stopped in four of 12. Median progression-free survival from the start of therapy was 5.3 months (95% confidence interval: 3.6-6.1), and median overall survival was 9.5 months (95% confidence interval: 7.7-13.5). A total of 20 patients were surviving at the cutoff date. Univariate analysis of age, sex, ulceration status, thickness, stage, location, or lactate dehydrogenase did not reveal significant predictors of progression-free survival or overall survival within our cohort, but multivariate analysis suggested that older age, lower risk location of original lesion, and nodular melanoma are poor prognostic indicators. Combination therapy with BRAF/MEK inhibitors is a viable treatment option for patients with BRAF-mutant melanoma and brain metastases, but further studies should help to define the optimal treatment approach in this population

CERN’s beam instrumentation R&D study for FCC-ee

The Future Circular Collider (FCC) R&D study was started in 2021 as a comprehensive feasibility analysis of CERN’s future accelerator project encompassing technical, administrative and financial aspects. As part of the study, Beam Instrumentation (BI) is a key technical infrastructure that will have to face unprecedented challenges. In the case of electron-positron FCC-ee, these are represented, among others, by the size of the accelerator, the amount of radiation produced along the ring and in machine-detector interaction region, the presence of the top-up booster and collider ring in the same tunnel. In this contribution we will present the current FCC-ee BI study and discuss its status and perspectives

Carriers of ADAMTS13 Rare Variants Are at High Risk of Life-Threatening COVID-19

Thrombosis of small and large vessels is reported as a key player in COVID-19 severity. However, host genetic determinants of this susceptibility are still unclear. Congenital Thrombotic Thrombocytopenic Purpura is a severe autosomal recessive disorder characterized by uncleaved ultra-large vWF and thrombotic microangiopathy, frequently triggered by infections. Carriers are reported to be asymptomatic. Exome analysis of about 3000 SARS-CoV-2 infected subjects of different severities, belonging to the GEN-COVID cohort, revealed the specific role of vWF cleaving enzyme ADAMTS13 (A disintegrin-like and metalloprotease with thrombospondin type 1 motif, 13). We report here that ultra-rare variants in a heterozygous state lead to a rare form of COVID-19 characterized by hyper-inflammation signs, which segregates in families as an autosomal dominant disorder conditioned by SARS-CoV-2 infection, sex, and age. This has clinical relevance due to the availability of drugs such as Caplacizumab, which inhibits vWF-platelet interaction, and Crizanlizumab, which, by inhibiting P-selectin binding to its ligands, prevents leukocyte recruitment and platelet aggregation at the site of vascular damage

Gain- and Loss-of-Function CFTR Alleles Are Associated with COVID-19 Clinical Outcomes

Carriers of single pathogenic variants of the CFTR (cystic fibrosis transmembrane conductance regulator) gene have a higher risk of severe COVID-19 and 14-day death. The machine learning post-Mendelian model pinpointed CFTR as a bidirectional modulator of COVID-19 outcomes. Here, we demonstrate that the rare complex allele [G576V;R668C] is associated with a milder disease via a gain-of-function mechanism. Conversely, CFTR ultra-rare alleles with reduced function are associated with disease severity either alone (dominant disorder) or with another hypomorphic allele in the second chromosome (recessive disorder) with a global residual CFTR activity between 50 to 91%. Furthermore, we characterized novel CFTR complex alleles, including [A238V;F508del], [R74W;D1270N;V201M], [I1027T;F508del], [I506V;D1168G], and simple alleles, including R347C, F1052V, Y625N, I328V, K68E, A309D, A252T, G542*, V562I, R1066H, I506V, I807M, which lead to a reduced CFTR function and thus, to more severe COVID-19. In conclusion, CFTR genetic analysis is an important tool in identifying patients at risk of severe COVID-19