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The United Nations 'quasi-prosecutorial' investigative mechanisms: assessing a new institutional model in the international criminal justice landscape
No full textThis work aims to provide a theoretical examination of three recently created bodies of the United Nations mandated to investigate the alleged international crimes committed in Syria (IIIM), Iraq (UNITAD) and Myanmar (IIMM). Established as a compromise solution in the paralysis of international criminal jurisdictions, these essentially overlapping entities have been depicted as a ‘new generation’ of UN investigative mechanisms. While non-judicial in nature, they depart indeed from traditional commissions of inquiry in several respects due to their increased criminal or ‘quasi-prosecutorial’ character. After clarifying their legal basis and different mandating authorities, a comparative institutional analysis is thus carried out in order to ascertain whether these ‘mechanisms’ can be said to effectively represent a new institutional model. Through an in-depth assessment of their mandates, the thesis is also intended to outline both the strengths and the criticalities of these organs. Given their aim to facilitate criminal proceedings by sharing information and case files, it is suggested that more attention shall be paid to the position of the person under investigation. To this end, some proposals are made in order to enhance the mechanisms’ frameworks, especially from the angle of procedural safeguards. As a third aspect, the cooperation with judicial authorities is explored, in order to shed light on the actors involved, the relevant legal instruments and the possible obstacles, in particular from a human rights perspective. Ultimately, drawing from the detected issues, the thesis seeks to identify some lessons learned which could be taken into account in case of creation of new ad hoc investigative mechanisms or of a permanent institution of this kind
Design, synthesis and photovoltaic properties of some thiophene-based conjugated polymers for organic solar cells
No full textThe current issue of the resource of energy combined with the tendency to give a green footprint to our lifestyle have prompted the research to focus the attention on alternative sources with great strides in the optimization of polymeric photovoltaic devices.
The research work described in this dissertation consists in the study of different semiconducting π-conjugated materials based on polythiophenes (Chapter I). In detail, the GRIM polymerization was deepened defining the synthetic conditions to obtain regioregular poly(3-alkylthiophene) (Chapter II). Since the use of symmetrical monomers functionalized with oxygen atom(s) allows to adopt easy synthesis leading to performing materials, disubstituted poly(3,4-dialkoxythiophene)s were successfully prepared, characterized and tested as photoactive materials in solar cells (Chapter III).
A “green” resource of energy should be employed through sustainable devices and, for this purpose, the research work was continued on the synthesis of thiophene derivatives soluble in eco-friendly solvents. To make this possible, the photoactive layer was completely tailored starting from the electron-acceptor material. A fullerene derivative soluble in alcohols was successfully synthetized and adopted for the realization of the new devices (Chapter IV).
New water/alcohol soluble electron-donor materials with different functional groups were prepared and their properties were compared (Chapter V).
Once found the best ionic functional group, a new double-cable material was synthetized optimizing the surface area between the different materials (Chapter VI).
Finally, other water/alcohol soluble materials were synthetized, characterized and used as cathode interlayers in eco-friendly devices (Chapter VII).
In this work, all prepared materials were characterized by spectroscopy analyses, gel permeation chromatography and thermal analyses. Cyclic voltammetry, X-ray diffraction, atomic force microscopy and external quantum efficiency were used to investigate some peculiar aspects
Stayability in Italian Simmental dual-purpose cows: phenotypic and genetic associations
No full textIn recent years, dairy farmers have observed a substantial decrease in cows’ survival, with a direct negative consequence on the profitability. Shorter lifespan raises questions about animal welfare and farming conditions at which cows are exposed to. However, the length of productive life depends also on voluntary culling due to low productivity and, in dual-purpose breed, to low price of carcasses (meat). The general aim of the thesis was to investigate the genetic and phenotypic relationship of functional longevity with morphological features like muscularity and body condition score (BCS) and productive traits within Italian Simmental dual-purpose dairy cattle raised in Emilia-Romagna herds
Role of bioactive compounds in the gastrointestinal host-pathogen interaction of poultry and swine
No full textThe better understanding of mechanisms at the basis of host-pathogen interaction can represent a valid tool to increase productivity and contain economic losses in animal production through the maintenance of intestinal homeostasis.
With this project, three preliminary in vitro studies were conducted with the aim of investigating how bioactive compounds could influence mechanisms of host-pathogen interaction in poultry and swine. Different panels of nature identical compounds, medium chain fatty acids, and plant extracts were employed against strains of Salmonella Typhimurium, Brachyspira hyodysenteriae, and Salmonella Enteritidis, respectively. When bacterial field strains were tested, the comparison between natural compounds and antibiotics was examined, with the aim of evaluating the role of the substances in the antibiotic-resistance context.
Results demonstrate that bioactive compounds have positive effects on the host, the pathogen, or both in different experimental conditions. Additionally, when compared to antibiotics, bioactive compounds have proven to be valid alternatives to address the phenomenon of antibiotic resistance
Hetero-bifunctional molecules as possible therapeutics for the treatment of Alzheimer’s disease.
No full textAlzheimer’s disease (AD) is the most common form of dementia, currently affecting more than 50 million people worldwide. In recent years attention towards this disease has risen in search for discovery and development of a drug that can stop it. Indeed, therapies for AD provide only temporary symptomatic relief. The cause for the high attrition rate for AD drug discovery has been attributed to several factors, including the fact that the AD pathogenesis is not yet fully understood. Nevertheless, what is increasingly recognized is that AD is a multifactorial syndrome, characterized by many conditions which may lead to neuronal death.
Given this, it is widely accepted that a molecule able to modulate more than one target would bring benefit to the therapy of AD. In the first chapter of this thesis, there are reported two projects regarding the design and synthesis of new series of GSK-3/HDAC dual inhibitors, two of the main enzymes involved in AD. Two different series of compounds were synthesized and evaluated for their inhibitory activity towards the target enzymes. The best compounds of the series were selected for further biologic investigation to evaluate their properties. The second project focused on the design of non ATP-competitive GSK-3 inhibitors combined with HDAC inhibition properties. Also in this case, the best compounds of the series were selected for biologic investigation to further evaluate their properties.
In chapter 2, the design and synthesis of a GSK-3-directed Proteolysis Targeting Chimeras (PROTAC), a new technology in drug discovery that act through degradation rather than inhibition, is reported. The design and synthesis of a small series of GSK-3-directed PROTACs was achieved. In vitro assays were performed to evaluate the GSK-3-degradation ability, the effective involvement of E3 ubiquitine ligase in the process and their neuroprotective abilities
Multi-scale modeling of gas transport properties in semi-crystalline polymers
No full textThe research presented here aimed at modeling gas transport properties in semi-crystalline polymers with particular attention to hydrogen gas.
The first part of the work was dedicated to developing a multi-scale modeling approach for evaluating gas sorption in semi-crystalline High-Density Polyethylene which couples Lattice-Fluid theory with Molecular Dynamics simulations. The model belongs to the so-called 'constraint pressure models' which implicitly describe the perturbation induced by the impermeable crystalline domains on the amorphous matrix using a fictitious constraint pressure parameter. The second and main part of the work focused on the molecular reproduction and simulation of the explicit semi-crystalline material accounting for different intercalations between the two phases (surface fraction of tie-chains). Quantitative information on hydrogen sorption and diffusion coefficients were derived using Widom test particle insertion method and the Mean Square Displacement analysis coupled with a macroscopic model for the estimation of the crystallites' induced tortuosity, respectively. The permeability coefficient was finally estimated according to the solution-diffusion model. The results were in agreement with the experimental results obtained in an experimental campaign that was conducted in parallel and other literature references
The possible dual role of IF1 in tumor metabolism: its contribution to the Warburg effect and promotion of anoxic tumor cell proliferation after re-oxygenation
No full textTumour cells exhibit high expression of IF1, an endogenous protein that inhibits the hydrolytic activity of ATP synthase under conditions of reduced mitochondrial membrane potential (∆μH+), as occurs in ischaemia. The pro-oncogenic effects of the inhibitor include the reprogramming of cellular energy metabolism towards the Warburg effect, which is promoted by IF1 in the dephosphorylated state. Both metabolic reprogramming and its PKA-dependent phosphorylation are highly controversial. To clarify these critical points, stable clones with silenced IF1 were generated and compared with parental IF1-expressing tumour cell lines. Bioenergetic parameters such as respiration rate, ATP synthesis rate (OXPHOS) and mitochondrial membrane potential were similar in IF1-silenced and control cells. This clearly shows that IF1 does not inhibit ATP synthase in tumour cells when the enzyme functions physiologically. Furthermore, cells showed a similar OXPHOS rate when exposed to positive and negative PKA modulators and stimulated with NAD+ or FAD-dependent substrates, regardless of the presence or absence of IF1. Consequently, the results of this work exclude the dependence of the effect of IF1 on its phosphorylated/dephosphorylated state. Our study clearly shows that IF1 does not inhibit mitochondrial ATP synthase or OXPHOS in normoxic tumour cells, thus invalidating its putative contribution to the Warburg effect. The role of IF1 as a pro-oncogenic factor is to protect tumour cells from apoptosis and severe hypoxia. We have investigated its influence on cancer cell survival and proliferation under conditions mimicking ischaemia-reperfusion. Experiments with IF1-silenced and parental cells exposed to the FCCP uncoupler showed that mitochondrial mass was preserved in all uncoupled cells. IF1-expressing cells exhibited increased mitophagy, which was balanced by mitochondrial biogenesis, resulting in a higher energy charge and a proliferative advantage upon re-oxygenation. IF1 proves to be a promising therapeutic target against OXPHOS-dependent tumours
Acquired and inherited cardiomyopathies: evaluation of cardiotoxic effects in preclinical models
No full textCardiomyopathies are a heterogeneous group of myocardial disorders defined by structural and functional alterations of the heart. These cardiac diseases can have both non-genetic and genetic origin. Nevertheless, a different etiology can trigger the same phenotype, as in the case of anthracycline-induced cardiotoxicity and desmin-related cardiomyopathy (DRM). Therefore, the aim of this study was to investigate the cellular mechanisms driving the development of these cardiotoxic conditions in in vitro models.
Doxorubicin (DOX) is a commonly used antineoplastic drug for the treatment of a wide range of tumors. Besides, its clinical use is restricted because of dose-dependent cardiotoxicity.
Our findings provided evidence that phospholipase C Beta 2 (PLCβ2) may have a critical role in DOX-induced cardiotoxicity in undifferentiated and differentiated H9c2 cell line. Interestingly, the results obtained revealed that cardiomyocytes are less sensitive to DOX, following the evaluation of cellular mechanisms such as: oxidative stress, apoptosis and cell proliferation. Nonetheless, the treatment induced a significant upregulation of PLCβ2 associated to morphological changes in both models, demonstrating the implication in a hypertrophic response.
On the other hand, a hereditary DRM was associated to a missense mutation of aB crystallin (CRYAB), a chaperone protein involved in the regulation of the intermediate filament network. Since research has only been conducted on transgenic (TG) mice and neonatal rat cardiomyocytes, this study aimed at investigating cellular mechanisms triggered by CRYABR120G mutation in a hiPSC-derived DRM model.
Our model confirmed the impairment of the cytoskeletal organization resulting in the formation of desmin and CRYAB aggregates and myofibril misalignment. Moreover, the missense mutation confirmed a hypertrophic cardiomyopathy phenotype, a feature of DRM patients, on cardiac engineered tissues.
Lastly, these data obtained suggest that further research on PLCβ2 and CRYAB are needed to comprehend the molecular mechanisms behind the development of these 2 cardiac diseases
Skeletal variability of the fibular ends and evolutionary implications
No full textThis thesis investigates the morphological variations of fibular extremities in humans and non-human hominids using a 3D Geometric Morphometric approach. The study has three objectives: (1) to assess the shape, form, and size variations of fibular epiphyses within the human species, highlighting sexually dimorphic features; (2) to explore interpopulation variability of fibular extremities from the Upper Paleolithic to the 20th century, comparing subsistence, mobility, and lifestyles; and (3) to examine interspecific variations in fibular ends, testing potential associations with locomotor and positional behavior among extant hominid taxa.
In terms of intraspecific variations, sex-related differences in fibular form and size were observed, suggesting distinct functional requirements for the lower limb between sexes. Interpopulation variations revealed a decline in activity level over time, influenced by terrain and footwear use. Hunter-gatherer groups exhibited greater joint mobility, loading, and range of motion compared to sedentary pre- and post-industrial populations.
Interspecific variations demonstrated significant morphological differences among hominid taxa, indicating functional implications related to both phylogeny and specific loading patterns on the lower limb. The study identified features indicative of bipedalism in humans, as well as shared characteristics among non-human great apes. Furthermore, distinguishing features were found between Asian and African apes, along with unique morphological signals associated with distinct positional behavior in each hominid taxa.
By comprehensively analyzing fibular morphology, this research sheds light on the importance of this bone in knee support, ankle stabilization, and overall locomotor function. The findings contribute to our understanding of the evolutionary and functional aspects of the fibula across human populations and non-human hominids throughout history
Resetting SETD2/H3K36ME3 deficiency in advanced systemic mastocytosis
No full textSystemic Mastocytosis (SM) is a hematological disorder characterized by abnormal proliferation of mast cells in various organs, ranging from indolent variants to advanced entities with poor prognosis. The KIT D816V gene mutation drives mast cell growth, but its presence alone is not fully transforming. The SETD2 gene, responsible for maintaining genomic integrity, is often impaired in advanced SM (advSM), leading to reduced expression of histone marker H3K36Me3. Proteasome inhibitors are effective in restoring SETD2 function and suppressing mast cell growth, offering an alternative therapy for patients resistant to tyrosine kinase inhibitors. Aberrant expression of Plk1 and Aurora kinase A correlates with SETD2 loss and can be targeted with inhibitors like alisertib and volasertib, leading to reduced cell growth and apoptosis. Additionally, inhibition of Wee1 enhances apoptosis and reduces colony growth in SM cells. Molecular diagnostic techniques like droplet digital polymerase chain reaction (ddPCR) offer a less invasive and reliable method for detecting the D816V mutation in peripheral blood, and efforts to standardize molecular assays across laboratories show promising reproducibility. Overall, this research provides new insights into the mechanisms of advanced SM, identifies potential therapeutic targets, and validates molecular diagnostic tools for SM diagnosis