Synthesis and Chemical Optimization of New Melatonergic Ligands, including Multitarget Compounds

Complex multifactorial pathologies, such as metabolic syndrome, psychiatric or degenerative central nervous system disorders, and cancer, are often caused by deregulation of multiple pathways, and cannot be effectively treated with a single-target modulation. Therefore, the use of multitarget compounds represents a more valid and effective strategy for these pathologies. Both melatonin and endocannabinoid are pleiotropic signaling system involved in all aspects of mammalian physiology and pathology, and for this reason they represents potential targets for the design and development of new therapeutic drugs. In my thesis work, I focused my attention on the synthesis of a different series of melatoninergic ligands, including new multitarget compounds able to also modulate the endocannabinoid system. The single enantiomers of (±)-UCM1014, a potent and selective MT2-receptor agonist, were obtained through an appropriate optical resolution strategy. Pharmacological experiments demonstrated that (R)-UCM1014 is the eutomer, with about 160-fold selectivity for the MT2 receptor and full agonist behaviour. The combination of molecular docking simulations and investigation of the conformational equilibria in solution by molecular dynamics simulations and NMR spectroscopy allowed us to rationalize the stereoselective behavior shown by the two enantiomers. New melatonergic fluorescent probes were synthetized, introducing on the C-4 position of MLT indole a formyl moiety (CHO) and a cyano (CN) group. The 4-CHO-MLT and the 4-CN-MLT gave the desired red-shifted absorption and emission spectra, but a diminished binding affinity for the two receptors was observed. The chemical optimization of UCM765, a MT2 partial agonist, lead to the synthesis of a new series of N-anilinoethylamide derivatives, characterized by improved water solubility and increased metabolically stability. Different elements were considered for the optimization of this important classes of melatonergic ligands, including the study of the size and the orientation of substituents of the aromatic scaffold as well as the introduction of more hydrophilic groups, enhancing the water solubility, or protecting metabolically liable positions while preserving the high binding affinity and selectivity toward the MT2 receptor. Finally, dual MLT agonists-MAGL (monoacylglycerol lipase) inhibitors with suitable physicochemical properties have been obtained by fusion of the pharmacophore elements required at the two targets. The new dual-acting compounds displayed good to moderate activity at the melatonergic and endocannabinoid systems. The most active compound, resulting from the combination of N-anilinoethylamide scaffold with the O-hexafluoroisopropanol carbamate, is characterized by a balanced activity at both targets, and is currently under investigation for neuroprotective and anti-inflammatory effects in vivo.Complex multifactorial pathologies, such as metabolic syndrome, psychiatric or degenerative central nervous system disorders, and cancer, are often caused by deregulation of multiple pathways, and cannot be effectively treated with a single-target modulation. Therefore, the use of multitarget compounds represents a more valid and effective strategy for these pathologies. Both melatonin and endocannabinoid are pleiotropic signaling system involved in all aspects of mammalian physiology and pathology, and for this reason they represents potential targets for the design and development of new therapeutic drugs. In my thesis work, I focused my attention on the synthesis of a different series of melatoninergic ligands, including new multitarget compounds able to also modulate the endocannabinoid system. The single enantiomers of (±)-UCM1014, a potent and selective MT2-receptor agonist, were obtained through an appropriate optical resolution strategy. Pharmacological experiments demonstrated that (R)-UCM1014 is the eutomer, with about 160-fold selectivity for the MT2 receptor and full agonist behaviour. The combination of molecular docking simulations and investigation of the conformational equilibria in solution by molecular dynamics simulations and NMR spectroscopy allowed us to rationalize the stereoselective behavior shown by the two enantiomers. New melatonergic fluorescent probes were synthetized, introducing on the C-4 position of MLT indole a formyl moiety (CHO) and a cyano (CN) group. The 4-CHO-MLT and the 4-CN-MLT gave the desired red-shifted absorption and emission spectra, but a diminished binding affinity for the two receptors was observed. The chemical optimization of UCM765, a MT2 partial agonist, lead to the synthesis of a new series of N-anilinoethylamide derivatives, characterized by improved water solubility and increased metabolically stability. Different elements were considered for the optimization of this important classes of melatonergic ligands, including the study of the size and the orientation of substituents of the aromatic scaffold as well as the introduction of more hydrophilic groups, enhancing the water solubility, or protecting metabolically liable positions while preserving the high binding affinity and selectivity toward the MT2 receptor. Finally, dual MLT agonists-MAGL (monoacylglycerol lipase) inhibitors with suitable physicochemical properties have been obtained by fusion of the pharmacophore elements required at the two targets. The new dual-acting compounds displayed good to moderate activity at the melatonergic and endocannabinoid systems. The most active compound, resulting from the combination of N-anilinoethylamide scaffold with the O-hexafluoroisopropanol carbamate, is characterized by a balanced activity at both targets, and is currently under investigation for neuroprotective and anti-inflammatory effects in vivo

MicroRNAs: tiny players with a big role in the pathogenesis of leukemias and lymphomas

MicroRNAs (miRNAs) are small non-coding RNAs (ncRNAs) with important regulatory functions. After an initial phase, aimed at identifying whether a deregulation in miRNA expression occurred between hematologic malignancies and their normal counterparts, currently an increasing number of studies are focusing on the functional significance of these aberrancies. The identification of miRNA targeted genes has cast a new light on the role of these tiny ncRNAs in human cancerogenesis, providing a new rationale to the observed diagnostic, prognostic and therapeutic implications of miRNA aberrant expression in human hematologic malignancies

Temporal Lensing: An Interactive and Scalable Technique for Web3D/WebXR Applications in Cultural Heritage

Today, Web3D technologies and the rise of new standards, combined with faster browsers and better hardware integration, allow the creation of engaging and interactive web applications that target the field of cultural heritage. Functional, accessible, and expressive approaches to discovering the past starting from the present (or vice-versa) are generally a strong requirement. Cultural heritage artifacts, decorated walls, etc. can be considered as palimpsests with a stratification of different actions over time (modifications, restorations, or even reconstruction of the original artifact). The details of such an articulated cultural record can be difficult to distinguish and communicate visually, while entire archaeological sites often exhibit profound changes in terms of shape and function due to human activities over time. The web offers an incredible opportunity to present and communicate enriched 3D content using common web browsers, although it raises additional challenges. We present an interactive 4D technique called "Temporal Lensing", which is suitable for online multi-temporal virtual environments and offers an expressive, accessible, and effective way to locally peek into the past (or into the future) by targeting interactive Web3D applications, including those leveraging recent standards, such as WebXR (immersive VR on the web). This technique extends previous approaches and presents different contributions, including (1) a volumetric, temporal, and interactive lens approach; (2) complete decoupling of the involved 3D representations from the runtime perspective; (3) a wide range applications in terms of size (from small artifacts to entire archaeological sites); (4) cross-device scalability of the interaction model (mobile devices, multi-touch screens, kiosks, and immersive VR); and (5) simplicity of use. We implemented and developed the described technique on top of an open-source framework for interactive 3D presentation of CH content on the web. We show and discuss applications and results related to three case studies, as well as integrations of the temporal lensing with different input interfaces for dynamically interacting with its parameters. We also assessed the technique within a public event where a remote web application was deployed on tablets and smartphones, without any installation required by visitors. We discuss the implications of temporal lensing, its scalability from small to large virtual contexts, and its versatility for a wide range of interactive 3D applications

Model Prediksi Dropout Mahasiswa Menggunakan Teknik Data Mining

Salah satu permasalahan yang ada di Perguruan Tinggi XYZ adalah tingginya jumlah mahasiswa yang putus studi (dropout / DO), sehingga diperlukan upaya untuk minimalisasi jumlah mahasiswa yang dropout.  Penelitian ini bertujuan untuk membangun sebuah model yang dapat memprediksi apakah seorang mahasiswa akan lulus ataukah dropout. Data diambil dari data akademis mahasiswa angkatan 2014-2019. Pemrosesan awal data dilakukan dengan Python dan pemodelan dilakukan dengan menggunakan algoritma C4.5 / J48 pada perangkat lunak WEKA (Waikato Environment for Knowledge Analysis). Hasil menunjukkan bahwa atribut yang paling menentukan apakah seorang mahasiswa DO atau lulus adalah Indeks Prestasi Semester 1 dan Indeks Prestasi Semester 2, dengan akurasi model mencapai sebesar 90.6%

Heritage education through serious games. A web-based proposal for primary schools to cope with distance learning

[EN] In recent years a growing amount of research has shown interest in studying how virtual reality (VR) could be relevant in many fields. In this respect, VR has gained consideration throughout many applications such as education. Among other aims for its use in education, serious games based on VR were used to promote heritage and make students experience either far or inaccessible scenarios. Until now, VR-based applications have been mainly implemented using head mounted displays (HMD), which actually reduced their circulation. This gap is particularly remarkable in the current Sars-CoV19 pandemic because students, being at home or being at school without sharing equipment, cannot exploit educational programs based on this technology. The current paper proposes a web-based platform on which VR applications could be accessed on any device, either desktop- or mobile-based. The serious game was initially set up on a computer with a specialized software using a HMD, while the process of turning it into a web-based platform is described so that the used methodology could be available to those, who would like to follow it. This project is probably also able to cope with the general aim of making inaccessible objects available to students and, thus, to make the application useful even beyond the current pandemic emergency.The VAR.HEE. project – Virtual and Augmented Reality for Heritage and art Education in school and museum Experiences – was funded by the Free University of Bozen/Bolzano with a competitive call for proposals by the Central Research Commission in 2017. The project lasts three years, started in January 2018 and will end in December 2020 (June 2021, after Covid-19 health emergency).Luigini, A.; Fanini, B.; Basso, A.; Basso, D. (2020). Heritage education through serious games. A web-based proposal for primary schools to cope with distance learning. VITRUVIO - International Journal of Architectural Technology and Sustainability. 5(2):73-85. https://doi.org/10.4995/vitruvio-ijats.2020.14665OJS73855

Relationships between the dynamics of two Talitrus saltator populations and the impacts of activities linked to tourism

The study considered two ecologically similar coastal areas in Tuscany (Italy).One site belongs to a protected natural area and the other one is infront of a camping site. We analysed the impact of human activities,such as trampling and mechanical beach cleaning, on Talitrus saltator.It turned out that the population density was affected in that it firstdisappeared from the area at the camping site, then recolonised it once the peak of the touristseason at the camping site had passed. The results confirm the sensitivityof this species and its plasticity in adapting to different conditions onthe one hand, and the positive effects of diversification in resourcemanagement on the other hand

Álgebras de divisão e aplicações

Orientador: Carlos Eduardo Durán FernándezTrabalho de Conclusão de Curso (graduação) - Universidade Federal do Paraná, Setor de Ciências Exatas, Curso de Graduação em MatemáticaInclui referênciasNão inclui resum

Dívida pública mobiliária e mercado de títulos públicos

Orientador: Francisco Paulo CipollaTese (doutorado) - Universidade Federal do Paraná, Setor de Ciencias Sociais Aplicadas, Programa de Pós-Graduaçao em Desenvolvimento Econômico. Defesa: Curitiba, 2005Inclui bibliografia e anexosÁrea de concentraçao: Políticas de desenvolviment