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Spectrum sensing in wireless communications serves as a crucial binary classification tool in cognitive radios, facilitating the detection of available radio spectrums for secondary users, especially in scenarios with high Signal-to-Noise Ratio (SNR). Leveraging Liquid State Machines (LSMs), which emulate spiking neural networks like the ones in the human brain, prove to be highly effective for real-time data monitoring for such temporal tasks. The inherent advantages of LSM-based recurrent neural networks, such as low complexity, high power efficiency, and accuracy, surpass those of traditional deep learning and conventional spectrum sensing methods. The architecture of the liquid state machine processor and its training methods are crucial for the performance of an LSM accelerator. This thesis presents one such LSM-based accelerator that explores novel architectural improvements for LSM hardware. Through the adoption of triplet-based Spike-Timing-Dependent Plasticity (STDP) and various spike encoding schemes on the spectrum dataset within the LSM, we investigate the advantages offered by these proposed techniques compared to traditional LSM models on the FPGA. FPGA boards, known for their power efficiency and low latency, are well-suited for time-critical machine learning applications. The thesis explores these novel onboard learning methods, shares the results of the suggested architectural changes, explains the trade-offs involved, and explores how the improved LSM model's accuracy can benefit different classification tasks. Additionally, we outline the future research directions aimed at further enhancing the accuracy of these models. / Master of Science / Machine Learning (ML) and Artificial Intelligence (AI) have significantly shaped various applications in recent years. One notable domain experiencing substantial positive impact is spectrum sensing within wireless communications, particularly in cognitive radios. In light of spectrum scarcity and the underutilization of RF spectrums, accurately classifying spectrums as occupied or unoccupied becomes crucial for enabling secondary users to efficiently utilize available resources. Liquid State Machines (LSMs), made of spiking neural networks resembling human brain, prove effective in real-time data monitoring for this classification task. Exploiting the temporal operations, LSM accelerators and processors, facilitate high performance and accurate spectrum monitoring than conventional spectrum sensing methods. The architecture of the liquid state machine processor's training and optimal learning methods plays a pivotal role in the performance of a LSM accelerator. This thesis delves into various architectural enhancements aimed at spectrum classification using a liquid state machine accelerator, particularly implemented on an FPGA board. FPGA boards, known for their power efficiency and low latency, are well-suited for time-critical machine learning applications. The thesis explores onboard learning methods, such as employing a targeted encoder and incorporating Triplet Spike Timing-Dependent Plasticity (Triplet STDP) in the learning reservoir. These enhancements propose improvements in accuracy for conventional LSM models. The discussion concludes by presenting results of the architectural implementations, highlighting trade-offs, and shedding light on avenues for enhancing the accuracy of conventional liquid state machine-based models further.

Photosensitizing effects of xenobiotics are of increasing concern in public health since modern lifestyle often associates sunlight exposure with the presence of chemical substances in the skin. An important number of chemicals like perfumes, sunscreen components, or therapeutic agents have been reported as photosensitizers. In this context, a considerable effort has been made to design a model system for photosafety assessment. Indeed, screening for phototoxicity is necessary at the early phase of drug discovery process, even before introducing drugs and chemicals into clinical therapy, to prevent undesired photoreactions in humans. In the case of new pharmaceuticals, their phototoxic potential has to be tested when they absorb in the regions corresponding to the solar spectrum, that is, for wavelengths >290 nm. So, there is an obvious need for a screening strategy based on in vitro experiments. The goal of the present thesis was the photochemical study of different photoactive drugs to investigate the key molecular aspects responsible for their photosensitivity side effects. In a first stage, rosuvastatin was considered in chapter 3 as representative compound of the statin family. This lipid-lowering drug, also known as “superstatin”, contains a 2-vinylbiphenyl-like moiety and has been previously described to decompose under solar irradiation, yielding stable dihydrophenanthrene analogues. During photophysical characterization of rosuvastatin, only a long-lived transient at ca. 550 nm was observed and assigned to the primary photocyclization intermediate. Thus, the absence of detectable triplet-triplet absorption and the low yield of fluorescence ruled out the role of the parent drug as an efficient sensitizer. In this context, the attention was placed on the rosuvastatin main photoproduct (ppRSV). Indeed, the photobehavior of this dihydrophenanthrene-like compound presented the essential components needed for an efficient biomolecule photosensitizer i.e. (i) a high intersystem crossing quantum yield (ΦISC =0.8), (ii) a triplet excited state energy of ca. 67 kcal mol−1 , and (iii) a quantum yield of singlet oxygen formation (Φ∆) of 0.3. Furthermore, laser flash photolysis studies revealed a triplet-triplet energy transfer from the triplet excited state of ppRSV to thymidine, leading to the formation of cyclobutane thymidine dimers, an important type of DNA lesion. Finally, tryptophan was used as a probe to investigate the Type I and/or Type II character of ppRSV-mediated oxidation. In this way, both an electron transfer process giving rise to the tryptophanyl radical and a singlet oxygen mediated oxidation were observed. On the basis of the obtained results, rosuvastatin, through its major photoproduct ppRSV, should be considered as a potential sensitizer. Then, itraconazole (ITZ), a broad-spectrum antifungal agent, was chosen as main character of chapter 4. Its photochemical properties were investigated in connection with its reported skin photosensitivity disorders. Steady state photolysis, fluorescence and phosphorescence experiments were performed to understand ITZ photoreactivity in biological media. The drug is unstable under UVB irradiation, suffering a primary dehalogenation of the 2,4-dichlorophenyl moiety that occurs mainly at the ortho-position. In poorly H-donating solvents, as acetonitrile, the major photoproduct arises from intramolecular attack of the initially generated aryl radical to the triazole ring. In addition, reduced compounds resulting from homolytic cleavage of the C-Cl bond in ortho or para positions and subsequent Habstraction from the medium are obtained to a lesser extent. In good H-donating solvents, such as ethanol, the main photoproducts are formed by reductive dehalogenation. Furthermore, irradiation of a model dyad containing a tryptophan unit and the reactive 2,4-dichlorophenyl moiety of itraconazole leads to formation of a new covalent link between these two substructures revealing that homolysis of the C-Cl bond of ITZ can result in alkylation of reactive amino acid residues of proteins, leading to formation of covalent photoadducts. Therefore, it has been established that the key process in the photosensitization by itraconazole is cleavage of the carbon-halogen bond, which leads to aryl radicals and chlorine atoms. These highly reactive species might be responsible for extensive free radical-mediated biological damage, including lipid peroxidation or photobinding to proteins. In chapter 5, photobehavior of imatinib (IMT) was addressed. This is a promising tyrosine kinase inhibitor used in the treatment of some types of human cancer, which constitutes a successful example of rational drug design based on the optimization of the chemical structure to reach an improved pharmacological activity. Cutaneous reactions, such as increased photosensitivity or pseudoporphyria, are among the most common nonhematological IMT side effects; however, the molecular bases of these clinical observations have not been unveiled yet. Thus, to gain insight into the IMT photosensitizing properties, its photobehavior was studied together with that of its potentially photoactive anilino-pyrimidine and pyridyl-pyrimidine fragments. In this context, steady-state and time resolved fluorescence, as well as laser flash photolysis experiments were run, and the DNA photosensitization potential was investigated by means of single strand breaks detection using agarose gel electrophoresis. The obtained results revealed that the drug itself and its anilino-pyrimidine fragment are not DNA-photosensitizers. By contrast, the pyridyl-pyrimidine substructure displayed a marked photogenotoxic potential, which was associated with the generation of a long-lived triplet excited state. Interestingly, this reactive species was efficiently quenched by benzanilide, another molecular fragment of IMT. Clearly, integration of the photoactive pyridyl-pyrimidine moiety in a more complex structure strongly modifies its photobehavior, which in this case is fortunate as it leads to an improved toxicological profile. Thus, on the bases of the experimental results, direct in vivo photosensitization by IMT seems unlikely. Instead, the reported photosensitivity disorders could be related to indirect processes, such as the previously suggested impairment of melanogenesis or the accumulation of endogenous porphyrins. Finally, a possible source of errors in the TEMPO/EPR method for singlet oxygen detection was analyzed. For many biological and biomedical studies, it is essential to detect the production of 1O2 and to quantify its production yield. Among the available methods, detection of the characteristic 1270 nm phosphorescence of singlet oxygen by time-resolved near infrared (TRNIR) emission constitutes the most direct and unambiguous approach. An alternative indirect method is electron paramagnetic resonance (EPR) in combination with trapping. This is based on the detection of the TEMPO free radical formed after oxidation of TEMP (2,2,6,6- tetramethylpiperidine) by singlet oxygen. Although the TEMPO/EPR method has been largely employed, it can produce misleading data. This was demonstrated by the present study, where the quantum yields of singlet oxygen formation obtained by TRNIR emission and by the TEMPO/EPR method were compared for a set of well-known photosensitizers. The results revealed that the TEMPO/EPR method leads to significant overestimation of singlet oxygen yield when the singlet or triplet excited state of the photosensitizers were efficiently quenched by TEMP, acting as electron donor. In such case, generation of the TEMP+• radical cation, followed by deprotonation and reaction with molecular oxygen gives rise to a EPR detectable TEMPO signal that is not associated with singlet oxygen production. This knowledge is essential for an appropriate and error-free application of the TEMPO/EPR method in chemical, biological and medical studies. / Nardi, G. (2014). MECHANISTIC STUDIES ON THE PHOTOTOXICITY OF ROSUVASTATIN, ITRACONAZOLE AND IMATINIB [Tesis doctoral no publicada]. Universitat Politècnica de València. https://doi.org/10.4995/Thesis/10251/48535 / TESIS

Ferromagnétisme et supraconductivité sont habituellement considérés comme deux ordres antagonistes, aussi la découverte de leur coexistence dans URhGe et UGe2 a généré beaucoup d'intérêt. Le mécanisme expliquant un tel état n'a cependant pas encore était totalement élucidé. La supraconductivité dans ces composés serait non conventionnelle: les fluctuations magnétiques pourraient être responsables de l'appariement des électrons en paires de Cooper avec des spins parallèles.<br /><br />Cette thèse porte sur l'étude du composé ferromagnétique supraconducteur URhGe. URhGe devient ferromagnétique en dessous d'une température de Curie de 9,5 Kelvin, avec des moments spontanés alignés selon l'axe c de sa structure orthorhombique. Pour des températures inférieures à 260 mK et des champs plus petits que 2 Tesla, une phase supraconductrice a été observée dès 2001. Au cours de cette thèse une deuxième phase supraconductrice induite sous champ a été mise en évidence dans des monocristaux pour des hauts champs magnétiques appliqués selon l'axe b des cristaux. Cette deuxième poche de supraconductivité enveloppe une transition métamagnétique ayant lieu pour un champ de 12 Tesla. Nous présentons dans ce manuscrit une étude détaillée de cette supraconductivité et de sa relation avec la transition métamagnétique. Nous discutons de l'existence d'un point critique quantique dans le diagramme de phase magnétique et du rôle des fluctuations magnétiques émergeant de ce point critique quantique dans le mécanisme d'appariement des électrons.

This thesis presents an experimental study of the superconducting proximity effect in sub-micrometer sized ferromagnetic discs. Such discs belong to a class of mesoscopic ferromagnets intermediate between microscopic magnets with dimensions below about 10nm that behave as single giant spins and macroscopic structures that are larger than approximately 1 micrometer where domains are formed to minimise stray fields. The magnetic structure of mesoscopic magnets is strongly dependent on their geometric shape, allowing for purposeful engineering of magnetic structures using modern lithographic techniques. The ground magnetic state of mesoscopic ferromagnetic discs is the magnetic vortex where unusual time-asymmetric triplet superconductivity is predicted to exist and survive up to the non-magnetic coherence length, that is orders in magnitude larger than the ferromagnetic singlet coherence length. Magnetic Force Microscopy (MFM) was used to directly study the magnetic structure of the discs. To detect the proximity effect in the vortices, Andreev interferometers were used with normal parts replaced with mesoscopic ferromagnetic discs in the magnetic vortex state. The samples were fabricated using electron-beam lithography and a modified shadow evaporation technique developed within this project, allowing the whole structure to be made with highly precise alignment, without breaking vacuum and avoiding redundant ferromagnetic elements disturbing the magnetic vortices. Observations were made of superconducting phase periodic oscillations in the conductance of the Andreev interferometers. Such oscillations provide unambiguous evidence of phase coherent electron transport through the ferromagnetic vortex. Finally, further experiments are discussed that would provide a more detailed understanding of the long range proximity effect in SFS junctions.

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Malgré des progrès importants réalisés ces dernières années, la lutte contre les infections virales (SIDA, hépatites etc.) et les cancers demeurent un problème de santé mondiale. Ce bref bilan met en évidence la nécessité de développer de nouvelles molécules pour contourner les limites des traitements disponibles actuellement. Cette thèse, articulée autour de trois grands thèmes, s’inscrit dans ce contexte. Nous avons d’abord mis au point de manière rationnelle de nouveaux ligands d’ARN capables de se lier sélectivement à certaines structures secondaires de type tige-boucle ou tige-renflement de l’ARN TAR du VIH-1. Ces ligands interagissent avec l’ARN grâce à l’action coopérative de deux motifs de reconnaissance : (i) une nucléobase modifiée qui peut reconnaitre spécifiquement une paire de base de l’ARN et (ii) des acides aminés qui agissent avec les bases non appariées de l’ARN. Ces deux motifs sont reliés grâce à une matrice aliphatique (ligands non nucléosidiques) ou une matrice 2-désoxyribose (ligands nucléosidiques). Des études biophysiques et biologiques ont été menés en collaboration avec l’équipe du Dr. L. Briant (CEAPBS, UMR5236-CNRS) pour connaitre leur activité antivirale et leur site d’interaction sur la cible. Nous avons ensuite développé des molécules de type benzènesulfonamide thiazoles pour cibler le mélanome résistant aux inhibiteurs de B-Raf. Des modulations effectuées sur ce squelette nous ont permis d’établir des relations structure/activité, en collaboration avec l’équipe de Dr. S. Rocchi (C3M, INSERM U895). Enfin, nous avons développé une stratégie de modification post-synthétique d’oligonucléotides en position anomérique par réaction clic. / Despite significant progress made in recent years, the fight against viral infections (AIDS, Hepatitis, etc.) and cancer remains a global health problem. This brief summary underlines the need for new compounds in order to overcome the limitations of currently available drugs. To this end, the main objective of this thesis is to address these issues by the investigation of three major research projects. We first developed new RNA ligands that selectively bind to RNA secondary structures such as the stem-loop or the stem-bulge of HIV-1 TAR RNA. These ligands interact with RNA thanks to the presence of two RNA binding domains acting in a cooperative manner: (i) a modified nucleobase that can specifically recognize an RNA base pair and (ii) basic amino acids that interact with strong affinity with surrounding free RNA nucleobases. These two patterns are connected by an aliphatic matrix (non-nucleoside ligands) or a 2-desoxyribose matrix (nucleoside-based ligands). Biophysical and biological studies were conducted in collaboration with the team of Dr. L. Briant (CEAPBS, UMR5236-CNRS) in order to study their antiviral activity and their mode of action. We next developed new bioactive molecules featuring a thiazole benzenesulfonamide scaffold to target melanoma cells resistant to B-Raf inhibitors. The modular synthesis of a large number of analogs allowed us to establish the structure/activity relationships, in collaboration with the team of Dr. S. Rocchi (C3M, INSERM U895). Finally, we developed a straightforward and convenient strategy for post-synthetic modification of oligonucleotides at the anomeric position using click chemistry.