Consensus for Mussolini? popular opinion in the province of Venice (1922-1943)

The thesis focuses on the response of Venice province population to the rise of Fascism and to the regime’s attempts to fascistise Italian society. This thesis is developed around analysis of popular opinion and the way in which limited local consensus for the Fascist regime contributed to Fascism’s downfall. The thesis begins with a discussion of the Party, and to provides a clear picture of how ‘national’ and ‘local’ interacted alongside the establishment of the structures. The focus then shifts to the working class and the way it came to terms with the Fascist regime. The third chapter deals with two groups that provided a particular challenge to the regime’s totalitarian aspirations: Venetian Youth and the Catholic Church with its attempts to resist and to jeopardize the regime’s intention to monopolise every aspect of social life. The fourth chapter is a case-study of the Venetian Jewish community, of how the Race Laws affected the life of Venetian Jews. Lastly, the fifth chapter, by way of a conclusion, studies the ‘Fascist War’ (1940-1943) as a microcosm that explains for the local Venetian context how the lack of popular consent enhanced the regime’s inability to survive war-induced challenges

Chitosan-Coated Nanoparticles: Effect of Chitosan Molecular Weight on Nasal Transmucosal Delivery

Drug delivery to the brain represents a challenge, especially in the therapy of central nervous system malignancies. Simvastatin (SVT), as with other statins, has shown potential anticancer properties that are difficult to exploit in the central nervous system (CNS). In the present work the physico⁻chemical, mucoadhesive, and permeability-enhancing properties of simvastatin-loaded poly-ε-caprolactone nanocapsules coated with chitosan for nose-to-brain administration were investigated. Lipid-core nanocapsules coated with chitosan (LNCchit) of different molecular weight (MW) were prepared by a novel one-pot technique, and characterized for particle size, surface charge, particle number density, morphology, drug encapsulation efficiency, interaction between surface nanocapsules with mucin, drug release, and permeability across two nasal mucosa models. Results show that all formulations presented adequate particle sizes (below 220 nm), positive surface charge, narrow droplet size distribution (PDI < 0.2), and high encapsulation efficiency. Nanocapsules presented controlled drug release and mucoadhesive properties that are dependent on the MW of the coating chitosan. The results of permeation across the RPMI 2650 human nasal cell line evidenced that LNCchit increased the permeation of SVT. In particular, the amount of SVT that permeated after 4 hr for nanocapsules coated with low-MW chitosan, high-MW chitosan, and control SVT was 13.9 ± 0.8 μg, 9.2 ± 1.2 µg, and 1.4 ± 0.2 µg, respectively. These results were confirmed by SVT ex vivo permeation across rabbit nasal mucosa. This study highlighted the suitability of LNCchit as a promising strategy for the administration of simvastatin for a nose-to-brain approach for the therapy of brain tumors

Nasal powders for delivery of disease modifying agents in early treatment of Alzheimer’s disease: formulation and characterization

The research conducted during this Ph.D. led to the development of a first prototype of a 2-drug powder formulation for nasal delivery with interesting features for the management of Alzheimer’s disease. First of all, the study proposed a flurbiprofen powder with suitable characteristics for nasal administration and nose-to-brain targeting. The powder comprised spray-dried flurbiprofen sodium microparticles, fast dissolving and sustaining extensive drug transport ex vivo across a model tissue of nasal mucosa. The construction of the final nasal dosage form continued through the agglomeration of the flurbiprofen microparticles with spray-dried excipient microparticles. In a rat animal model both flurbiprofen microparticles and agglomerates allowed for the drug to enter the central nervous system and enhanced its brain disposition compared to systemic drug administration by intravenous injection. The combination of flurbiprofen spray-dried microparticles with a second drug in powder form was the next step to better address Alzheimer’s disease by the so-called “multi-target approach”. To this purpose, insulin spray-dried microparticles were studied and combined with flurbiprofen ones in form of agglomerates for nasal delivery.Il lavoro condotto in questo Dottorato di ricerca ha portato allo sviluppo di una formulazione in polvere per la veicolazione nasale di due sostanze attive per il trattamento del morbo di Alzheimer. Dapprima è stata sviluppata una polvere di flurbiprofene con caratteristiche adatte alla somministrazione nasale e alla veicolazione naso-cervello del farmaco. La polvere consisteva in microparticelle spray-dried di flurbiprofene sodico, caratterizzata da rapida dissoluzione e capace di produrre un trasporto ex vivo di farmaco attraverso un tessuto modello di mucosa nasale. La costruzione di una forma di dosaggio nasale finale è continuata attraverso l’agglomerazione delle microparticelle di flurbiprofene con microparticelle spray-dried di eccipiente. In un modello animale murino le microparticelle e gli agglomerati di flurbiprofene hanno consentito al farmaco di entrate nel sistema nervoso centrale e hanno aumentato la sua disponibilità nel cervello rispetto alla somministrazione sistemica di flurbiprofene per via endovenosa. L’ultima fase del lavoro è stata la combinazione di microparticelle spray-dried di flurbiprofene con una seconda sostanza attiva in forma di polvere per il cosiddetto “approccio multi-target” per il trattamento della malattia di Alzheimer. A questo scopo, sono state studiate microparticelle spray-dried di insulina e combinate con quelle di flurbiprofene in forma di agglomerati

STUDI SPERIMENTALI SUL MECCANISMO DELLA DISTROFIA DA MUTAZIONE A CARICO DEI GENI CODIFICANTI PER IL COLLAGENE VI

Mutations of genes coding for collagen VI are responsible, in humans, of congenital muscular dystrophies, giving rise to three syndromes Bethlem Myopathy (BM), Ullrich Congenital Muscular Dystrophy (UCMD) and Congenital Myosclerosis (CM). Based on the high degree of heterogeneity and the overlap between them, it has been proposed that these disorders may represent a clinical continuum rather than strictly separated entities, and that there may be a wider spectrum of collagen VI related disorders. Despite these major advances in understanding their genetic bases, the molecular pathogenesis remained partially obscure. As it is the case for many genetic diseases, creation of animal models may be the key to understand the physiopathology, and to devise and test potential therapies. Several years ago (Bonaldo at al, 1998) a mutant mouse with targeted inactivation of COL6A1 gene, coding for the 1(VI) chain, was created. In the absence of a 1(VI) chain, collagen VI does not assemble and is not secreted in the extracellular matrix, and therefore homozygous null mice (Col6a1-/-) completely lack collagen VI in their tissues. These mice are affected by early onset myopathic disease with weakness and histological alterations of skeletal muscles. Col6a1-/- muscle have loss of contractile strength with ultrastructural alterations of sarcoplasmic reticulum (SR) and mitochondria and spontaneous apoptosis. There is a latent mitochondrial dysfunction in myofibers which can be revealed upon incubation with the selective F1F0-ATPase inhibitor oligomycin, which causes mitochondrial depolarization, Ca2+ deregulation and increased apoptosis. These defects were reversible, as they can be normalized by plating Col6a1-/- myofibers on collagen VI or by addition of cyclosporin A (CsA), the inhibitor of mitochondrial permeability transition pore (PTP). Collagen VI myopathies, in mice and humans, can be effectively treated with drugs acting downstream on pathogenic lesion. These observations lead to the hypothesis that the lack of collagen VI causes an increased probability of opening of the PTP, but we don’t know through which signalling pathway the lack of collagen VI in the extracellular matrix can have effects on mitochondria. One important partner of collagen VI is the proteoglycan NG2. In particular, there is evidence that NG2 binds to collagen VI via a protein-protein interaction (Tillet et al, 1997). NG2 may be considered an important receptor mediating collagen VI-sarcolemma interactions and this relationship may be disrupted in the pathogenesis of Bethlem and Ullrich dystrophies. We also know that the perturbation of NG2 distribution on the cell surface results in parallel change in collagen VI distribution (Nishiyama et al,1997). The NG2-collagen VI interaction may be important for organization of the extracellular matrix, for binding of cells to the matrix, for determination of cell morphology in relation to the matrix, and for a transduction of transmembrane signalling. To clarify the relevance of NG2 for muscle function and structure, muscles of mice carrying a null mutation of NG2 were studied. The aim of this study was a comparative characterization (in vivo, ex vivo and in vitro) of the phenotype of muscles from ColVI-/- and NG2-/- mice and the evaluation of the differences between the two models to understand in what way the absence of these proteins might lead to mitochondrial damage. The experimental program was aimed to the characterization of muscles from C57BL/6, Col6a1-/- and NG2-/- mice in vivo, ex vivo ed in vitro. The integrity of the membrane was tested with the blue Evans dye which allows to detect, pointed out with blue color, muscle fibers in which the sarcolemma has been damaged. At first the analysis of functional parameters of muscle contraction was carried out in vivo, with the following tests: - mouse force (Grip test) - force developed by the muscle gastrocnemius during isometric contraction. Then the analysis of functional parameters was developed ex vivo: - intact muscle diaphragm, EDL, soleus dissected and analysed in myograph - electrophoresis of proteins from diaphragm, EDL, soleus - histological and histochemical analysis of gastrocnemius and tibial. Finally, single muscle fibres were kept in culture and studied, in vitro: - recording Ca2+ transient in single fibres of FDB - electrophoresis of single fibres - immunocytochemistry analyses. The results of all the above listed tests have shown that the two phenotypes have only a partial overlap and, thus, NG2 does not represent the only structural/functional connection between Collagen VI in the ECM and the intracellular processes in muscle fibres. The role of integrin require to be explored.Le mutazioni dei geni che codificano per le subunità del collagene VI sono una delle cause delle patologie muscolari ereditarie umane che si manifestano come la Miopatia di Bethlem (BM), la Distrofia Muscolare Congenita di Ullrich (UCMD) e la Miosclerosi Congenita (CM). Basandosi sull’alto grado di eterogeneità e di parziale sovrapposizione tra di loro, è stato proposto che questi disordini possano rappresentare un “continuum” clinico piuttosto che entità strettamente separate, e che ci possa essere un più ampio spettro di disordini connessi al collagene VI. Nonostante i grandi progressi nella comprensione delle loro basi genetiche, la patogenesi molecolare rimane ancora in parte sconosciuta. Come nel caso di molti difetti genetici, la creazione di animali transgenici può essere la chiave per comprendere la fisiopatologia e per mettere a punto, e testare, potenziali terapie. Molti anni fa (Bonaldo et al, 1998) è stato creato un topo mutante con inattivazione mirata del gene COL6A1, che codifica per la catena 1(VI). In assenza della catena 1(VI), il collagene non è assemblato e non è secreto nella matrice extracellulare, e pertanto il topo omozigote mutante (Col6a1-/-) perde il collagene VI nei suoi tessuti. I topi sono affetti da un disordine miopatico ad esordio precoce con debolezza e cambiamenti istologici del muscolo scheletrico. I muscoli del Col6a1-/- perdono forza contrattile e mostrano alterazioni ultrastrutturali a livello del reticolo sarcoplasmatico (SR), dei mitocondri e apoptosi spontanea. E’ presente una disfunzione mitocondriale latente nelle miofibre che si può evidenziare con incubazione con oligomicina, inibitore della F1F0-ATPasi, che causa depolarizzazione mitocondriale, de-regolazione del Ca2+ e aumento dell’apoptosi. Questi difetti sono reversibili, e possono essere normalizzati piastrando le fibre muscolari di Col6a1-/- su collagene VI o somministrando cisclosporina A (CsA), un inibitore del poro di transizione di permeabilità mitocondriale (PTP). Le miopatie dovute al collagene VI, sia umane che negli animali, possono essere efficacemente trattate con tale farmaco che agisce a valle della lesione patogenetica (Irwin et al, 2003 e Merlini et al, 2008). Così queste osservazioni portano ad ipotizzare che la mancanza del collagene VI causa un aumento dell’apertura del PTP ma non è ancora noto per mezzo di quale via di segnale. Un importante partner del collagene VI è il proteoglicano NG2. In particolare, ci sono prove che NG2 si leghi al collagene VI attraverso un interazione proteina-proteina (Tillet et al, 1997). NG2 può essere considerato un importante mediatore dell’interazione collagene VI-sarcolemma e il venir meno di questa relazione potrebbe avere un ruolo nella patogenesi delle distrofie di Bethlem e Ullrich. Sappiamo inoltre che modificazioni nella distribuzione superficiale di NG2 porta ad un parallelo cambiamento nella distribuzione del collagene VI (Nishiyama et al,1997). L’interazione NG2-collagene VI può essere importante nell’organizzazione della matrice, per il legame delle cellule alla matrice, per determinare la morfologia cellulare in risposta alla matrice, e per la trasduzione del segnale transmembrana. Per chiarire l’importanza di NG2 per la funzione e la struttura muscolare, sono stati studiati muscoli di topi con mutazione di NG2. Lo scopo dello studio è la caratterizzazione fenotipica comparativa (in vivo, ex vivo and in vitro) di Col6a1-/- and NG2-/- e la valutazione delle differenze tra i due modelli per comprendere se la mancanza di queste proteine porti ad un simile danno nella fibra muscolare. Si è proceduto dapprima a saggiare l’integrità della membrana con il colorante vitale blue Evans che permette di rilevare, evidenziandole con colorazione blu, le fibre muscolari il cui sarcolemma ha subito un danno. Poi, si è passati quindi all’analisi dei parametri funzionali della contrazione muscolare in vivo quali: - sviluppo di forza (Grip test) - sviluppo della forza massimale del gastrocnemio stimolato per via nervosa. Successivamente è stata effettuata una valutazione ex vivo: - meccanica dei muscoli interi diaframma, EDL e soleo - elettroforesi delle proteine muscolari - analisi istochimiche di gastrocnemio e tibiale. Infine per avere un quadro completo si è continuata l’ indagine in vitro : - transienti di calcio su singole fibre di FDB - elettroforesi su singole fibre di FDB - analisi immunocitochimiche. I risultati di tali analisi hanno mostrato che i due fenotipi hanno solamente una parziale sovrapposizione e quindi NG2 non rappresenta l’unica via di mediazione della presenza del collagene VI. Il ruolo delle integrine richiede di essere esplorato

Automatic generation of trajectories for collaborative robots in the presence of obstacles

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Recent Trends in&nbsp;Mobile Robotics for&nbsp;3D Mapping in&nbsp;Agriculture

This article presents trends and future developments in mobile robotics for 3D mapping in agriculture. Recent examples of robotic platforms and sensors are first presented to highlight the technologies adopted for autonomous surveying in the agricultural field. Then, localization and mapping approaches are discussed, as well as path planning algorithms for the navigation of mobile robots in orchards and crops. Finally, insights into applications of artificial intelligence to robotic mapping are given to evaluate the potentiality of neural networks in this field. The results of the survey indicate research directions and suggest future applications of mobile robotics as an efficient tool for smart agriculture

Experimental Evaluation and&nbsp;Comparison of&nbsp;LiDAR SLAM Algorithms for&nbsp;Mobile Robotics

This paper presents an experimental evaluation and comparison of LiDAR SLAM algorithms for mobile robotics. We analyze the performance of four state-of-the-art methods for localization and mapping in terms of the capability in reconstructing a point cloud of the surveyed environment and of the required computational effort. More in detail, the cloud-to-cloud distance with respect to a ground-truth reference model and the density of the final point cloud are evaluated and compared. Experimental tests are conducted by performing repeated autonomous surveys on two different scenarios with a mobile robot, showing the advantages and disadvantages of the considered methods in reconstructing a 3D map

Chitosan coated human serum albumin nanoparticles: A promising strategy for nose-to-brain drug delivery

The aim of the present study was the development of human serum albumin nanoparticles (HSA NPs) as nose-to-brain carrier. To strengthen, the efficacy of nanoparticles as drug delivery system, the influence of chitosan (CS) coating on the performance of HSA NPs was investigated for nasal application. HSA NPs were prepared by desolvation technique. CS coating was obtained adding the CS solution to HSA NPs. The mean particle sizes was 241 ± 18 nm and 261 ± 8 nm and the ζ-potential was −47 ± 3 mV and + 45 ± 1 mV for HSA NPs and CS-HSA NPs, respectively. The optimized formulations showed excellent stability upon storage both as suspension and as freeze-dried product after 3 months. The mucoadhesion properties were assessed by turbidimetric and indirect method. NPs were loaded with sulforhodamine B sodium salt as model drug and the effect of CS coating was investigated performing release studies, permeation and uptake experiments using Caco-2 and hCMEC/D3 cells as model of the nasal epithelium and blood-brain barrier, respectively. Furthermore, ex vivo diffusion experiments have been carried out using rabbit nasal mucosa. Finally, the ability of the formulations to reversibly open tight and gap junctions was explored by western blotting and RT-PCR analyzing in both Caco-2 and hCMEC/D3 cells

Opportunity and challenges of nasal powders: Drug formulation and delivery

© 2017 Elsevier B.V. In the field of nasal drug delivery, among the preparations defined by the European Pharmacopoeia, nasal powders facilitate the formulation of poorly water-soluble active compounds. They often display a simple composition in excipients (if any), allow for the administration of larger drug doses and enhance drug diffusion and absorption across the mucosa, improving bioavailability compared to nasal liquids. Despite the positive features, however, nasal products in this form still struggle to enter the market: the few available on the market are Onzetra Xsail® (sumatriptan) for migraine relief and, for the treatment of rhinitis, Rhinocort® Turbuhaler® (budesonide), Teijin Rhinocort® (beclomethasone dipropionate) and Erizas® (dexamethasone cipecilate). Hence, this review tries to understand why nasal powder formulations are still less common than liquid ones by analyzing whether this depends on the lack of (i) real evidence of superior therapeutic benefit of powders, (ii) therapeutic and/or commercial interest, (iii) efficient manufacturing methods or (iv) availability of suitable and affordable delivery devices. To this purpose, the reader's attention will be guided through nasal powder formulation strategies and manufacturing techniques, eventually giving up-to-date evidences of therapeutic efficacy in vivo. Advancements in the technology of insufflation devices will also be provided as nasal drug products are typical drug-device combinations