3,313 research outputs found


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    The development of new, potent and selective bacterial, viral and human sialidase (neuraminidase) inhibitors is an important issue to be pursued in order to achieve both useful therapeutical and biochemical tools. In fact, these hydrolytic enzymes can represent a good target since they play key roles in some physio-pathological processes by regulating the levels of sialic acid (such as the N-acetyl neuraminic acid; Neu5Ac) presents in glycoconjugates. In addition, in the design of inhibitors against a specific member of this class of enzymes is critical to take into account that these proteins share some common features such as the tridimensional structure of their catalytic domain, but, on the other hand, they show a very low sequence identity. Indeed, the only conserved residues are some active site amino acids essential for the catalytic mechanism. This thesis work was focused on the synthesis of hemagglutinin-neuraminidase (HN) inhibitors against the Newcastle virus (NDV), a member of the Paramyxoviridae family and strictly related to human parainfluenza viruses (hPIVs). NDV is a single-stranded RNA virus which could affect most species of both domestic and wild birds, causing significant and substantial economic losses in the poultry industry. To date, vaccination is the preferential instrument to border the infection, but when this procedure is not applicable, an efficient antiviral therapy could be the only useful way to control NDV outbreaks. At this purpose, the HN glycoproteins of paramyxoviruses represent an excellent target to be hit because they have some key roles in viral lifecycle: a) allowing viral attachment to the target cell; b) promoting the fusion process and, finally c) ensuring the release of the neo-synthesized virions. Over the past years, while some 2,3-unsaturated Neu5Ac derivatives (DANA derivatives) have been marketed as inhibitors against influenza virus neuraminidases (belonging to Orthomyxoviridae family), no compounds reach the clinical phase for paramyxoviruses treatment. In particular, few molecules have been developed for NDV-HN, and the N-trifluoroacetyl derivative of DANA (FANA) was still the best inhibitor until my thesis work. So, the necessity to find new, potent and possibly selective inhibitors against paramyxoviruses-HNs remain a key issue. At this purpose, the successful strategy, resulted fundamental to develop new NDV-HN inhibitors, was based on a multidisciplinary approach that combined the use of a) the chemical synthetic procedures, b) the computational docking studies and c) some biochemical activity assays. More in detail, the attention was directed to the study of two classes of inhibitors: \uf0a7 Some C5 or C4/C5 modified 2,3-unsaturated DANA derivatives, as reversible inhibitors. \uf0a7 Some scarcely investigated C2 modified 3,4-unsaturated Neu5Ac analogues, as irreversible ones. We finally reached satisfying results, regarding both classes of inhibitors: a) The understanding of the influence of the C5 N-perfluorinated substituents on the inhibitory activity of some 2,3-unsaturated DANA analogues, as potent and reversible NDV-HN inhibitors. b) The discovery of a new C5 N-perfluorinated inhibitor against NDV-HN as potent as FANA (the best NDV-HN inhibitor previously published) but more selective for NDV-HN towards human NEU3. c) The significant achievements of five new, potent and selective C4 and C5 modified 2,3-unsaturated DANA derivatives. All these compounds, combining the C4 azido or C4 p-toluensolfonamido group with the C5 N-perfluorinated chains, showed IC50 values in the nanomolar range; thus, they are up to 15-fold more potent than FANA. d) The set-up of more efficient synthetic procedures to achieve the 3,4-unsaturated Neu5Ac derivatives in high yields and \u3b2-anomeric stereoselectivity. e) The set-up of a smart and rapid method to unequivocally attribute the C2 configuration of the 3,4-unsaturated Neu5Ac inhibitors, via a 1,7-lactonization reaction. f) The mechanism elucidation of an unreported and unexpected chemical scrambling between the C4 and the C5 position of Neu5Ac derivatives (through a previously uncharacterized reaction intermediate). In addition, the rigid and induced fit docking simulation results permitted me to speculate on the interactions of the synthesized inhibitors with some active site amino acids, such as Lys236, a well know key residue involved in NDV-NH catalytic site activation mechanism and in fusion promotion activity. The comprehension of ligand/receptor interactions could lead to the development of molecules able to block, not only the neuraminidase activity of NDV-HN or other paramyxoviruses-HN, but also other viral functions mediated by these enzymes. Some of the obtained results allowed the publication of two scientific articles: \uf0a7 Rota, P., La Rocca, P., Piccoli, M., Montefiori, M., Cirillo, F., Olsen, L., Orioli, M., Allevi, P., and Anastasia, L. (2018) Potent Inhibitors against Newcastle Disease Virus Hemagglutinin-Neuraminidase, ChemMedChem 13, 236-240. \uf0a7 Rota, P., Papini, N., La Rocca, P., Montefiori, M., Cirillo, F., Piccoli, M., Scurati, R., Olsen, L., Allevi, P., and Anastasia, L. (2017) Synthesis and chemical characterization of several perfluorinated sialic acid glycals and evaluation of their in vitro antiviral activity against Newcastle disease virus, MedChemComm 8, 1505-1513

    Human brain distinctiveness based on EEG spectral coherence connectivity

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    The use of EEG biometrics, for the purpose of automatic people recognition, has received increasing attention in the recent years. Most of current analysis rely on the extraction of features characterizing the activity of single brain regions, like power-spectrum estimates, thus neglecting possible temporal dependencies between the generated EEG signals. However, important physiological information can be extracted from the way different brain regions are functionally coupled. In this study, we propose a novel approach that fuses spectral coherencebased connectivity between different brain regions as a possibly viable biometric feature. The proposed approach is tested on a large dataset of subjects (N=108) during eyes-closed (EC) and eyes-open (EO) resting state conditions. The obtained recognition performances show that using brain connectivity leads to higher distinctiveness with respect to power-spectrum measurements, in both the experimental conditions. Notably, a 100% recognition accuracy is obtained in EC and EO when integrating functional connectivity between regions in the frontal lobe, while a lower 97.41% is obtained in EC (96.26% in EO) when fusing power spectrum information from centro-parietal regions. Taken together, these results suggest that functional connectivity patterns represent effective features for improving EEG-based biometric systems.Comment: Key words: EEG, Resting state, Biometrics, Spectral coherence, Match score fusio

    Alkali-metal plasmons, pseudopotentials, and optical sum rules

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    Evolution equation for a model of surface relaxation in complex networks

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    In this paper we derive analytically the evolution equation of the interface for a model of surface growth with relaxation to the minimum (SRM) in complex networks. We were inspired by the disagreement between the scaling results of the steady state of the fluctuations between the discrete SRM model and the Edward-Wilkinson process found in scale-free networks with degree distribution P(k)∼k−λ P(k) \sim k^{-\lambda} for λ<3\lambda <3 [Pastore y Piontti {\it et al.}, Phys. Rev. E {\bf 76}, 046117 (2007)]. Even though for Euclidean lattices the evolution equation is linear, we find that in complex heterogeneous networks non-linear terms appear due to the heterogeneity and the lack of symmetry of the network; they produce a logarithmic divergency of the saturation roughness with the system size as found by Pastore y Piontti {\it et al.} for λ<3\lambda <3.Comment: 9 pages, 2 figure


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    Umbilical Cord Mesenchymal Stromal Cells for Cartilage Regeneration Applications

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    Chondropathies are increasing worldwide, but effective treatments are currently lacking. Mesenchymal stromal cell (MSCs) transplantation represents a promising approach to counteract the degenerative and inflammatory environment characterizing those pathologies, such as osteoarthritis (OA) and rheumatoid arthritis (RA). Umbilical cord-(UC-) MSCs gained increasing interest due to their multilineage differentiation potential, immunomodulatory, and anti-inflammatory properties as well as higher proliferation rates, abundant supply along with no risks for the donor compared to adult MSCs. In addition, UC-MSCs are physiologically adapted to survive in an ischemic and nutrient-poor environment as well as to produce an extracellular matrix (ECM) similar to that of the cartilage. All these characteristics make UC-MSCs a pivotal source for a stem cell-based treatment of chondropathies. In this review, the regenerative potential of UC-MSCs for the treatment of cartilage diseases will be discussed focusing on in vitro, in vivo, and clinical studies

    Educational cosmic-ray experiments with Geiger counters

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    Experiments concerning the physics of cosmic rays offer to highschool teachers and students a relatively easy approach to the field of research in high-energy physics. The detection of cosmic rays does not necessarily require the use of sophisticated equipment, and various properties of the cosmic radiation can be observed and analysed even by the use of a single Geiger counter. Nevertheless, the variety of such kind of experiments and the results obtained are limited because of the inclusive nature of these measurements. A significant improvement may be obtained when two or more Geiger counters are operated in coincidence. In this paper we discuss the potential of performing educational cosmic-ray experiments with Geiger counters. In order to show also the educational value of coincidence techniques, preliminary results of cosmic-ray experiments carried out by the use of a simple coincidence circuit are briefly discussed

    Influence of crop cycle and nitrogen manure form on yield and nitrate content of leafy, hypocotyl and fruit vegetables

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    Research was carried out in Latina province (Italy) on rocket, radish and zucchini grown under tunnel. Ten treatments, obtained by the factorial combination of two crop cycles (autumn-winter and winter-spring) and six nitrogen fertilizer forms (organic, organic-mineral, mineral in three modes, control with no nitrogen fer- tilization) were compared. The effects of these treatments were evaluated in terms of yield and nitrate content in the edible organs. In rocket, no significant difference in yield was detected between the autumn-winter and winter-spring crop cycles, although the former cycle resulted in a higher leaf nitrate content. The organic fertilizer treatment and the N-unfertilized control gave the lowest yields, but the mineral fertilizers caused the highest leaf nitrate accumulation. Radish yield did not vary between the two crop cycles, but the hypocotyl nitrate content was higher in the autumn-winter cycle. The crops fertilized with the two highest mineral supplies produced the highest yields, compared with the organic or organic-mineral treatments. In the autumn-winter crop, the mineral N fertilization resulted in the highest hypocotyl nitrate content, whereas in the winter-spring crop only the highest mineral N dose caused a higher nitrate content compared with the organic fertilizer. The highest zucchini yield was obtained from the winter-spring cycle at the two highest mineral fertilizer supplies. In the autumn-winter crop the highest mineral nitrogen dose resulted in the highest fruit nitrate content, while in winter-spring the two highest supplies caused this effect
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