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Multimodal representation and learning
No full textRecent years have seen an explosion in multimodal data on the web. It is therefore important to perform multimodal learning to understand the web. However, it is challenging to join various modalities because each modality has a different representation and correlational structure. In addition, various modalities generally carry different kinds of information that may provide enrich understanding; for example, the visual signal of a flower may provide happiness; however, its scent might not be pleasant. Multimodal information may be useful to make an informed decision. Therefore, we focus on improving representations from individual modalities to enhance multimodal representation and learning. In this doctoral thesis, we presented techniques to enhance representations from individual and multiple modalities for multimodal applications including classification, cross-modal retrieval, matching and verification on various benchmark datasets
Metal nanoparticle permeation through the plasma membrane: Xenopus laevis oocytes as novel tools for membrane permeability evaluation and physico-chemical characterization of particle properties.
No full textIn this Ph.D. thesis several kinds of metal-based NPs were tested in Xenopus laevis oocytes, in order to understand the metal NP related toxicity. The mechanism of the metals entrance in the cell and the passive permeation hypothesis were investigated. The results can be categorized as follows:
• The metallic NPs tested (Co, Fe, Ni) dissolve more than their oxide counterparts; however, they are unstable in suspension and their aggregation rate is fast. All these particles are not able to induce modifications in membrane biophysical parameters and in intracellular metal concentration, thereby excluding a direct membrane crossing mechanism for their internalization.
• The metal oxide NPs which retain a population below 200 nm (Fe3O4, Co3O4) in suspension in experimental medium induced significant modifications in membrane biophysical parameters and in intracellular metal concentration. The effects are recorded only when the population of NPs smaller than 200 nm is present, namely only within 5 min from the particles addition to the medium; after this time range, effects on membrane become milder until they disappear, stating the complete fast recovery of the membrane.
• The metal oxide NPs that never go below 200 nm (NiO, Fe2O3) in suspension in the experimental medium do not cross the membrane and do not modify neither intracellular metal concentration nor membrane biophysical parameters.
• The surface coating modifies particles behavior in suspension in the experimental medium. The non-covalent coating by BSA stabilized the 200 nm population for Co3O4 and Fe3O4 NPs but abolished the modifications in intracellular metal concentration and in membrane biophysical parameters. The covalent coating by APTES of Fe2O3 NPs partially stabilized particles around 100 nm but failed to induce membrane crossing. The role of particle surface is thus crucial to achieve direct membrane crossing.
Many of the studies conducted nowadays on direct membrane crossing rely on models, both in silico as well as in vitro, that are limited in replicating the biological complexity of the cells. Using voltage clamp and fluorescent probe on Xenopus Laevis oocytes may lay the foundation for an innovative screening platform, allowing to study the internalization and the effects on membrane. Xenopus laevis oocytes are easy to collect, maintain and prepare. They are flexible and adaptable to different culture conditions, allowing to study interactions in controlled environment.
Moreover, Xenopus laevis oocytes can also be a useful tool to study and optimize targeted internalization. Their historical use as heterologous expression system is well known, selectively express target proteins to study specific internalization pathways of new modified nanoparticles will be one of the new goals for the therapeutic use of nanomaterial
La giurisdizione in materia extracontrattuale nello spazio giudiziario europeo.
No full textArticles 7 n. 2 of Regulation No 1215/2012 and 5 n. 3 of the Lugano Convention of 2007 regulate jurisdiction in cross-border non-contractual matters.
Given the issues of interpretation concerning the jurisdictional criterion of the “place where the harmful event occurred” (so-called locus commissi delicti), the European Court of Justice: i) developed the ubiquity rule; ii) differently located the place of the event giving rise to the damage and the place where the damage occurred, depending on the type of tort; iii) specified the ubiquity rule with the rule of the initial event giving rise to the damage, the relevance of direct and nonconsequential damages, the mosaic principle and the principle of territoriality and iv) included a third jurisdictional criterion in online defamation and antitrust matters and derogated to the mosaic principle in national trade mark, antitrust and product liability matters.
In light of such a variety of interpretations, this thesis considers to develop a uniform interpretation of the locus commissi delicti in cybertorts in order to confirm the sole principle of ubiquity by attributing jurisdiction to the court of the place of establishment of the wrongdoer and to the court of the place of the center of interest of the victim of the tort. This solution is also confirmed by Article 79, paragraph 2, of Regulation No 2016/679.
Regarding cross-border collective actions, the thesis proposes to include in Article 7 n. 2 of Regulation No 1215/2012 the jurisdictional criterion of the “place where the majority of the harmful event occurred or may occur”, referring to both the place where the majority of the event giving rise to the damage occurred and to the place where the majority of the damage occurred.
This thesis also considers the coordination between Article 7 n. 2 of Regulation No 1215/2012 and Articles 79, paragraph 2, of Regulation No 2016/679, 122, paragraph 2, lett. a) of Regulation No 2017/1001, 79, paragraph 3, lett. a) of Regulation No 6/2002 and 31 of the Agreement on a Unified Patent Court
Parasite-host relationships in the biological control of insects: strategies of immunoevasion/immunosuppression and interference of temperature on the lethality of entomoparasites.
No full textIn this PhD project were considered two aspects of the relationship between bio-insecticide and insect hosts: the first has been the study the mechanisms carried out by EPNs complexes (Steinernema carpocapsae - Xenorhabdus nematophila) to overcome or neutralize the immune system of the insect host. The success of the EPNs results mainly from immunological disabling induced by nematode and its symbionts by immunoevasion/immunosuppression process when released inside the host hemocoel. The functions of structures and molecular components of the surface of both nematodes and bacteria play a key role and we assessed the role of protein pools isolated against Galleria mellonella (Lepidoptera).
The eluted compounds from live nematode possessed a slight cytotoxicity on the haemocytes, whereas those from live bacteria markedly affected the host cells’ viability. Bacterial proteins can inhibit the phagocytic activity, despite they strongly trigger the host prophenoloxidase-phenoloxidase system.
The second part of the project is aimed to acquire useful information on host-parasite relations in the context of climate change and, we reconsidered the physical conditions (such as temperature) in which bioinsecticides are highly effective. We evaluated the effectiveness of different commercial bio-insecticides (Steinernema feltiae, Steinernema carpocapsae, Heterorhabditis bacteriophora and Bacillus thuringiensis) assessing the mortality rate induced in two insect models, Galleria mellonella (Lepidoptera) and Sarcophaga africa (Diptera) after conditioning at various temperatures (10, 20 and 30 °C); moreover, we investigated the effects of temperature on the basal humoral immunity (phenoloxidase and lysozyme activity)
Atrofia Muscolare Spinale: presentazione clinica, quadri radiologici, nuovi trattamenti e biomarcatori
No full textSpinal Muscular Atrophy is an autosomal recessive disorder affecting 1:100,000 live births, in which survival motor neuron (SMN) protein deficiency leads to motor neuron degeneration and progressive muscle atrophy, weakness,and early mortality.
Most of SMA patients harbor homozygous SMN1 deletions while SMN2 copy number predicts the clinical subtype (SMA-I, -II, -III-IV). Few (3-5%) SMA patients display small mutations point mutations on the second allele. The behavior of point mutations in SMN1/SMN2 is heterogenous and requires proper validation.
In recent years the discovery of effective therapies has marked the history of Spinal Muscular Atrophy(SMA). The only currently approved drug is Nusinersen, which is an antisense oligonucleotide that binds to the SMN2 pre-mRNA downstream of exon 7,leading to the translation of a fully functional SMN protein. The treatment has opened up a new scenario with the creation of a new phenotypic spectrum.
We have studied prospectively patients treated with nusinersen, by planning serial evaluations : neurological exam, muscle strength (MRC), motor functional scales, timed tests, muscle MRI, CMAP and MUNE.
Monitoring long-term outcome measures will allow us to characterize the new phenotypes of the disease and to define the efficacy spectrum of Nusinersen in patients with different ages and degrees of motor impairment.
Neurofilament chains (Nf) are sensitive, liquor-based marker that can identify patients with neurodegenerative diseases, aid in the prediction of their long-term outcomes, and be used for assessing effects of treatment. At present, little is known about serum Nf levels in patients with SMA. To that purpose, we have measured the levels of Nf during the treatment with Nusinersen
Towards circular economy in developing cities: an integrated approach for planning international cooperation projects
No full textSolid waste management (SWM) issues are an environmental and social burden, which affect mainly the population of low-middle income countries worldwide, as well as the global environment. The application of the circular economy (CE) principles (reuse of waste materials) is considered the main solution spreading the economy of the waste and therefore reducing environmental impacts.
This research is focused on the analysis and application of integrated approaches for planning sustainable SWM systems in developing big cities, demonstrating the importance of the inclusion of the informal recycling and drafting international cooperation projects for introducing new appropriate technologies and awareness campaigns. The case study of this research is La Paz (Bolivia), low-middle income city where international support is required for the sustainable development.
The results allow suggesting that the inclusion of informal recyclers can be considered the most useful option in terms of technical and financial issues, exploiting a CE system just in place. Moreover, the cooperation with local and international stakeholders allows writing and submitting two international cooperation projects.
The research demonstrates that the cooperation among various international and local actors, such as Universities, non-governmental organizations and local Government, in parallel with the use of technical knowledge and methodologies can support the sustainable development in low-middle countries, driving low-middle income cities towards the CE
Discriminative feature learning for multimodal classification
No full textThe purpose of this thesis is to tackle two related topics: multimodal classification and objective functions to improve the discriminative power of features.
First, I worked on image and text classification tasks and performed many experiments to show the effectiveness of different approaches available in literature.
Then, I introduced a novel methodology which can classify multimodal documents using singlemodal classifiers merging textual and visual information into images and a novel loss function to improve separability between samples of a dataset.
Results show that exploiting multimodal data increases performances on classification tasks rather than using traditional single-modality methods.
Moreover the introduced GIT loss function is able to enhance the discriminative power of features, lowering intra-class distance and raising inter-class distance between samples of a multiclass dataset
La risicoltura italiana oltre la PAC: nuove opportunità e possibili strategie
No full textRice is the staple food of more than half of the world population and its availability is crucial to food security in a context of continuous demographic growth. Rice production also represents a fundamental economic activity: more than 110 countries are involved, generating a global paddy production of 759.6 million tonnes and an estimated international exchange of about 24.5 billion dollars. Likewise, rice production is strictly linked to social and environmental sustainability, as it is based on a complex ecological system, which has crucial influence on climate, biodiversity and landscape challenges.
Despite of its worldwide nature, rice market is highly concentrated. Italy has a key role since rice fields in the Po valley cover half of total EU28 production. Thanks to the agricultural self-sufficiency policy, Italian rice sector grew rapidly after the Second World War, highlighting the competitiveness of national producers and varieties. Nevertheless, in recent decades, the sector is wobbeling under the pressure of internal structural problems, combined with a global economic downturn and a critical evolution of the international commerce. A partial reduction of the number of farms as well as of the extension of cultivations, frequent price fluctuations and the fall of revenues, emphasise the presence of serious weaknesses and threats.
In such a context, the revision of the Common Agricultural Policy (CAP) is considered to be the main responsible of this crisis. Nevertheless, a critical overview underlines that it is only one of multiple interacting factors influencing rice market development, whereas lacks in business strategies and entrepreneurial culture determine a poor performance in this sector, at large. Moreover, CAP not only creates obstacles and limits to farmers’ activity, but also support innovative strategies for the renewal of this sector
Role of RNASET2 in innate immune response regulation
No full textNumerous studies have highlighted the existence of enzymes that, besides presenting a conserved role, take part in different biological processes acquiring new functions. In particular, the T2 RNase family of enzymes is one of the most investigated group, which is involved not only in RNA regulation, but also performs additional functions, regardless of the catalytic activity. It has been recently observed that, through the continuous cross-talk between the cancer cells and the adjacent microenvironment and the activation of inflammatory response by inducing macrophages activation, the human protein RNASET2 is able to control the ovarian cancer malignancy. However, the details about the mechanisms by which T2 enzymes interact with immune system remain poorly defined. The medicinal leech Hirudo verbana is here proposed as a consolidated invertebrate model to shed light on these aspects. The results presented in this project reveal that both human and leech T2 RNases cause fibroplasia, connective tissue remodeling and macrophage recruitment in leeches. Moreover, in vivo and in vitro experiments proved that HvRNASET2, released by granulocytes after bacterial infection, is a candidate molecule for counteracting pathogens. In particular, it plays a dual role, inducing bacterial clustering to facilitate macrophage phagocytosis and promoting immunocompetent cells recognition. In conclusion, HvRNASET2 acts as an effector of innate immune response, to favore an efficient microbial pathogen elimination and an effective oncosuppressive activity. These studies, related to roles of T2 RNases in tissue remodeling, immune response modulation and antimicrobial activity, could be essential for developing new therapeutic application
Axial stereogenicity for designing inherently chiral organic semiconductors.
No full textThe topic of my research is focused on the discovery and development of new inherently chiral molecules that, due to their peculiar properties, can be used both as semiconductive material and, when the molecules are deposited as an enantiopure film, as surfaces able to enantiorecognize chiral probes.
In the last years, the interest for the organic semiconductors has increased and especially multi-thiophene molecules have attracted considerable attention. Such multi-thiophene materials are obtained by chemical or electrochemical oxidation of a monomer and they are insulator in neutral state but become conductor after p- or n-type doping.
Chirality is generally introduced in the polyconjugated semiconductors by attaching chiral pendants to the electroactive backbone but these materials give relevant chirality manifestations only under particular experimental conditions [1]. The idea on which is based this research project is to design a class of compounds that could strictly correlate the conductive polythiophenes backbone to the chirality properties. This requirement is satisfied by the exploitation of the inherent chirality that is based on the concept that the scaffold constituting the stereogenic element responsible for chirality is also the functional group responsible for properties.
The peculiarities of the inherently chiral system are that the chirality results from a tailored torsion produced along the conducting oligothiophene backbone, the stereogenic core responsible for chirality is an atropoisomeric bi-thiophene or bi-pyrrole, and the same conjugated system responsible for the electro-optical properties is also responsible for molecular chirality.
The first member of this new class, nicknamed BT2T4 (because it consists in a bithianaphthene scaffold leading four thiophenes), showed outstanding properties such as a very high racemization barrier, great chiroptical properties and, deposited as an enantiopure polymeric film on an electrode, it showed amazing enantiorecognition ability [2].
Furthermore, BT2T4 was chemical oxidized by FeCl3 and the mixture of the oligomers was analyzed through HR MALDI spectrometry giving a very surprising result since all the oligomers, namely dimers, trimers and superior oligomers, were found to be cyclic and not open and linear [3].
Prompted by these outstanding results, during the first year of the PhD research we modified the structure of BT2T4 in order to obtain new inherently chiral compounds following two different strategies. The first one is based on the bithiophene tail elongation in order to achieve, after the oxidation, cyclic compounds with bigger cavity. The second strategy, on the other hand, aims to achieve a compound where the bithiophene tails are blocked in a rigid coplanar structure: the rigidity of the system indeed should provide material endowed with better optoelectronic properties.
All these compounds were prepared according to the same general procedure starting from the 2,2’-dibromo-3,3’- bithianaphatene that was functionalized with different “pendants” through a Stille reaction.
As shown in figure 2 the selected “pendants” were the ter-thiophene (BT2T6), the 3',4'-dibutyl-2,2':5',2''-terthiophene (BT2T6 Bu), the dithienopyrrole-N-octyl (BT2DTP2), the dithienopyrrole-N-methyl-phenyl (BT2DTP2 Ph) and the 4,7-di(thiophen-2-yl)benzo[c][1,2,5]thiadiazole (BT2BTD2).
In particular, the introduction of a benzothiadiazole system has a double role: to extend the pendant lenth and, at the same time, to lead to a compound exhibiting optical properties slightly different from the other monomers (i.e. high quantum yields and λ absorption red-shifted).
After one year, we reached many promising results: we could confirm that the modification introduced on the BT2 scaffold leads to monomers able to oligomerize through chemical and electrochemical oxidation producing cyclic oligomers with different dimension and shape. We analyzed both monomers and oligomers by different techniques. Futhermore, some of them were separated into enantiomers and their chiroptical properties were investigated.
As expected, the compound nicknamed BT2BTD2 has remarkable properties, especially from an optical point of view but unfortunately, we could not exploit it due to its low solubility. For this reason, we planned to modify the structure of the monomer in order to improve the solubility by introducing four EDOT units in place of the four thiophenes.
Unfortunately, due to the low solubility of the benzothiadiazole-bis-EDOT (BTDE) it was not possible to obtain the target monomer through the classical synthetic scheme which requires a Pd (0) catalyzed Stille reaction. However, since the bare BTDE appeared an interesting monomer, we investigated its chemical and electrochemical copolymerization in the presence of 3,3’-bithianaphtene. These experiments were carried out in the group of prof. S. Ludwigs of the University of Stuttgart, where I spent my abroad period, exploiting the expertise of the group in the polymer synthesis and electrochemical analysis.
Since both chemical and electrochemical oxidation did not give the expected results, we moved our attention to the possibility to achieve a donor-acceptor (D-A) copolymer by copolymerization of the benzothiadiazole-bis-EDOT with the branched terthiophene, nicknamed T3, deeply investigated in that group [4,5]. D-A polymers have recently attracted particular interest since they exhibit a reduced band-gap, due to their in-chain donor-acceptor interaction and for this reason they are used as light-harvesting system in solar cells. Furthermore, besides a long time focused on electrochemical analysis, during the period spent in Germany I synthetized two new compounds.
In order to investigate the role of ramification, we prepared a product with the same number of thiophenes as BT2T6 but with a branched structure by functionalizing the atropisomeric scaffold with two T3 units.
On the other hand, we synthetized a compound functionalized with four EDOT units, nicknamed BT2E4 which should have provided a material with interesting properties, being EDOT electron-richer than thiophene and ubiquitous in the electroactive materials.
During my third year, we focused our attention on a new class of inherently chiral monomer based on the scaffold of the 2,2’-biindole. The design of the new class has two main motivations:
the 2,2’-biindolic core is more electron rich than that of 3,3’-bithianaphtene and the first two oxidations result at an oxidative potential particularly low. This could allowed to discriminate analytes in a different potential window.
the nitrogen atom can be functionalized, tuning solubility and processability of the final material.
Especially interesting is the monomer derived from the introduction of a chiral pendant, namely the (R)- or (S)-phenylethyl group, that leads to the formation of two diastereoisomers, theoretically separable through a classical method, avoiding the chiral HPLC.
Indeed, the major disadvantage presented by the compounds investigated until now is the fact that their separation into antipodes must be performed through HPLC on a chiral stationary phase. Developing a method that could allow to avoid this tedious step would be an appealing target. In figure 5 are reported two other monomers synthetized according to this strategy: the first is characterized by the presence of two carboxylic groups that could allowed a classical resolution through the formation of diastereoisomeric salts with a chiral base. The second, on the other hand, was obtained as an enantiopure compound through an enantioselective synthesis starting from an enantiopure precursor obtained, in turn, by resolution with camphosulfonic acid.
In addition, due to the remarkable properties showed by BT2BTD2, we decided to introduce the benzothiadiazole system on the 2,2’-biindole scaffolds obtaining the first example of a biindole with a pendant different from the bithiophene. The presence of the nitrogen atoms allows the functionalization with two hexylic chains that strongly increase the solubility of the monomer, overcoming the problem found for BT2BTD2.
In conclusion, after three years research on inherently chiral electroactive materials new compounds, based on 3,3’-bithianaphtene and 2,2’-biindole core, were synthetized and fully characterized.
The new frontier of this kind of inherently chiral monomers results to be the achievement of enantiopure compounds without the use of chiral HPLC and some preliminary interesting results have been obtained.
[1] Janssen et al.; J. Molecular Structure, 2000, 521, 285;
[2] Sannicolò, F.; Benincori, T. et al.; Angew. Chem., Int Ed., 2014, 53, 2623;
[3] Sannicolò, F.; Benincori, T. et al.; Chemistry: an European Journal, 2014, 20, 15261;
[4] Link, S.; Ludwigs, S. et al.; Langmuir, 2013, 29, 15463;
[5] Goll, M.; Ludwigs, S. et al.; Beilstein J. Org. Chem, 2015, 11, 335;
[6] Abbiati, G.; Arcadi, A. el al.; Tetrahedron, 2006, 62, 3033