Progettazione e sintesi di nuovi antagonisti CB1 a struttura pirazolica come potenziali radiofarmaci per la PET imaging

Cannabinoid receptors are members of the large family of G-protein coupled receptors. Two types of cannabinoid receptor have been discovered: CB1 and CB2. CB1 receptors are localised predominantly in the brain whereas CB2 receptors are more abundant in peripheral nervous system cells. CB1 receptors have been related with a number of disorders, including depression, anxiety, stress, schizophrenia, chronic pain and obesity. For this reason, several cannabinoid ligands were developed as drug candidates. Among these ligands, a prominent position is occupied by SR141716 (Rimonabant), which is a pyrazole derivative with inverse agonist activity discovered by Sanofi-Synthelabo in 1994. This compound was marketed in Europe as an anti-obesity drug, but subsequently withdrawn due to its side-effects. Since the relationship between the CB1 receptors’ functional modification, density and distribution, and the beginning of a pathological state is still not well understood, the development of radio-ligands suitable for in vivo PET (Positron Emission Tomography) functional imaging of CB1 receptors remains an important area of research in medicine and drug development. To date, a few radiotracers have been synthesised and tested in vivo, but most of them afforded unsatisfactory brain imaging results. A handful of radiolabelled CB1 PET ligands have also been submitted to clinical trials in humans. In this PhD Thesis the design, synthesis and characterization of three new classes of potential high-affinity CB1 ligands as candidate PET tracers is described.

Caratterizzazione proteomica di fluidi e tessuti in diverse condizioni fisio-patologiche

This thesis has been focused on the proteomic characterization of human saliva from donors of different ages, starting from birth up to adult age, and pediatric brain tumor tissues. The first study has been performed in order to compare the acid-insoluble fraction of saliva from preterm with at-term newborns and adults and establish if differences exist. In the second study medulloblastoma and pilocytic astrocytoma pediatric brain tumor extracts have been compared. In both studies 2- DE analysis was coupled with high resolution tandem mass spectrometry (MS/MS). The proteomic characterization of the acid-insoluble fractions of saliva from preterm newborns allowed to integrate data previously obtained on the acid-soluble fraction by HPLC-electrospray ionization (ESI)-mass spectrometry (MS), and to evidence several differences between preterm newborns, at-term newborns and adults. Spots differentially expressed between the three groups, according to image analysis of the gels, were submitted to in-gel tryptic digestion and the peptide mixture analyzed by high performance HPLC-ESI-MS/MS for their characterization. By this strategy, we identified three over-expressed proteins in atterm newborns with respect to preterm newborns and adults (BPI fold-containing family A member 1, two proteoforms of annexin A1, and keratin type 1 cytoskeletal 13), and several over-expressed proteins in adults (fatty acid-binding protein, S100A6, S100A7, two proteoforms of S100A9, several proteoforms of prolactin-inducible protein, Ig kappa chain, two proteoforms of cystatin SN, one proteoform of cystatin S and several proteoforms of α-amylase 1). Moreover, for the first time, it was possible to assign by MS/MS four spots of human saliva 2-DE, already detected by other authors, to different proteoforms of S100A9. The strategy applied used a sequential staining protocol to the 2-DE gels, first with Pro-Q Diamond, that allows specific detection of phosphoproteins, and successively with total protein SYPRO Ruby stain. In the second study, proteomic analysis of two pediatric brain tumor tissues pointed out differences between medulloblastoma, the prevalent malignant tumor in childhood, and pilocytic astrocytoma, the most common, that only rarely shows a malignant progression. Due to the limited availability of bioptic tissue, the study was performed on pooled tumor tissues, and was focused on acid-insoluble fraction to integrate the characterization performed by a group of colleagues in Rome on the acid-soluble fraction by high performance HPLC-ESI-MS/MS. The results indicated that the two tumors exhibit different proteomic profiles and evidenced interesting differential expression of several proteins. Among them, peroxiredoxin- 1, peptidyl-prolyl cis–trans isomerase A, heterogeneous nuclear ribonucleoproteins A2/B1, mitochondrial isoform of malate dehydrogenase, nucleoside diphosphate kinase A, glutathione S-transferase P and fructose bisphosphate aldolase A resulted significantly over-expressed in medulloblastoma while glial fibrillary acidic protein, serotransferrin, α crystallin B chain, ferritin light chain, annexin A5, fatty acid-binding protein (brain), sorcin and apolipoprotein A-I resulted significantly over-expressed in pilocytic astrocytoma. In conclusion, the work done allowed to evidence the usefulness of using an integrated bottom-up/top-down approach, based on 2-DE-MS analysis and high performance MS in order to obtain a complete characterization of the proteome under investigation, revealing and identifying, not only peptides and small proteins, but also proteins with higher MW, that often it is not possible to identify by using exclusively a top-down ESI-MS approach.

Sopravvenienze e rimedi nel contratto d'appalto: la previsione del cosiddetto obbligo di rinegoziazione

In this thesis I study how the legal system reacts (or ought to react) to unforeseen circumstances that interfere with the functioning of long term contractual relationships. More precisely, I investigate whether mandatory renegotiation would be an appropriate tool to guarantee the flexibility that long-term relationships require. Furthermore, after having analyzed the instruments that our legal system offers to preserve long-term contractual relationships, I explore the solutions adopted by other legal systems. This comparative analysis helps to formulate normative proposals to improve the functioning of our legal system.

Risorse intangibili e imprese familiari: principali contributi sul tema e nuove prospettive di ricerca

Intangible resources are the distinctive factors for the success of businesses (Barney, 1991) and for this reason the literature has paid particular attention to this issue (Barney, 1991; Hall, 1992,1993; Carmeli, 2004; Galbreath, 2005; Hayton, 2005; Norman, Butler, Ranft, 2013). With this thesis I will analyze existing studies on the subject with particular reference to family businesses - ideal forum for the spread of specific intangibles (Ward, 1988; Habbershon, Williams, 1999; Sirmon & Hitt, 2003; Huybrechts et al., 2011; Rose, Howorth & Discua Cruz, 2014), in order to identify the main areas of research and new research perspectives. Through a narrative review on the general theme of intangible resources, bibliometric analysis of the contributions that jointly address the intangibles and family businesses and co-citation analysis for the definition of the intellectual structure of the studies on the intangible resources in family firms is reached an in-depth study of the issue with relevant academic and practical implications.

Caratterizzazione geo-petrografica, petrologica e geochimica di rocce anatettiche del nord Sardegna

The High Grade Metamorphic Complex (HGMC) of Variscan basement of north Sardinia is characterized by the widespread of migmatites. This study is focused on two localities of NE Sardinia (Porto Ottiolu and Punta Sirenella) where ortho- and para-derivates migmatites outcrop. A geological and structural survey was carried out, leading to the realization of a geological schematic map of Punta Sirenella area. Several samples of different rocks were collected for petrographic, micro-structural minero-chemical and geochemical analyses. In the Porto Ottiolu area three main deformation phases have been identified; D1, characterized by tight folds with sub-horizontal axes, rarely preserved in paragneisses; D2, that produce a pervasive foliation oriented N100° 45°SW marked by biotite and sillimanite blastesis and locally transposed by shear zone oriented N170°; D3, late deformation phase caused symmetric folds with sub-horizontal axes with no axial plane schistosity. Leucosomes form pods and layers along S2 schistosity but also leucosomes along shear zones have been observed. In the Punta Sirenella area, three main deformation phases have been identified; D1, is manifested by the transposition of centimeter-sized leucosomes and is rarely observed in paragneisses were produce open folds with sub-vertical axes; D2, NW-SE oriented on whose XY plane three mineralogical lineation (quartz+plagioclase, fibrolite+quarz and muscovite) lie; D3, a ductile-brittle deformation phase that produce a mylonitc S3 foliation that locally become the most evident schistosity in the field oriented N140° steeply dipping toward NE. In both areas, leucosomes of sedimentary-derived migmatites are generally trondhjemitic pointing out for a H2O fluxed melting reaction, but also granitic leucosomes have been found, produced by muscovite dehydration melting. Leucosomes of migmatitic orthogneiss instead, have granitic compositions. Migmatization started early, during the compressional and crustal thickening (sin-D1, pre-D2) and was still active during exhumation stage. For each studied outcrop of migmatite pseudosections for the average mesosome composition have been calculated; these pseudosections have been used to model the P-T conditions of anatexis on the basis of the melt volume (%) of melt, Si/Al and Na/K molar ratios, modal content of garnet and Si content in metamorphic white mica. Further pseudosections have been calculated for the average composition of leucosomes in order to define the P-T conditions of the end of the crystallization through intersection of solidus curve and isopleths of Si content in white mica and/or XMg ratio in biotite. Thermodynamic modeling on ortho- and sedimentary-derived migmatites of Punta Sirenella yield P-T conditions of 1.1-1.3 GPa - 670-740°C for migmatitic event and 0.75-0.90 GPa - 660-730°C for the end of crystallization. These conditions are fit well with previous studies on adjacent rocks. Modeling of Porto Ottiolu ortho- and sedimentary-derived migmatites yield P-T conditions of 0.85-1.05 GPa - 690-730°C for migmatitic event and 0.35-0.55 GPa - 630-690°C strongly affected by re-equilibration during exhumation, expecially for crystallization conditions. Geochemical analyses of samples belonging to Porto Ottiolu and Punta Sirenella orthogneisses show a strong link with those of other orthogneisses outcropping in NE Sardinia (for instance, Lode-Mamone and Golfo Aranci) that are considered the intrusive counterparts of middle-Ordovician metavolcanics rocks outcropping in the Nappe Zone. Thus, the studied ortogneiss bodies, even lacking radiometric data, can be considered as belonging to the same magmatic cycle.

Les manuscrits latins de la Chirurgia d'Albucasis et la lexicographie du latin m?di?val

Trotter, David, 'Les manuscrits latins de la Chirurgia d'Albucasis et la lexicographie du latin m?di?val', Archivum Latinitatis Medii Aevi (Bulletin Du Cange) (2001) 59(1) pp.181-202 RAE2008

Genome-scale analyses of health-promoting bacteria: probiogenomics

The human body is colonized by an enormous population of bacteria (microbiota) that provides the host with coding capacity and metabolic activities. Among the human gut microbiota are health-promoting indigenous species (probiotic bacteria) that are commonly consumed as live dietary supplements. Recent genomics-based studies (probiogenomics) are starting to provide insights into how probiotic bacteria sense and adapt to the gastrointestinal tract environment. In this Review, we discuss the application of probiogenomics in the elucidation of the molecular basis of probiosis using the well-recognized model probiotic bacteria genera Bifidobacterium and Lactobacillus as examples.

Comparison of deterministic, stochastic and fuzzy logic uncertainty modelling for capacity extension projects of DI/WFI pharmaceutical plant utilities with variable/dynamic demand

The last 30 years have seen Fuzzy Logic (FL) emerging as a method either complementing or challenging stochastic methods as the traditional method of modelling uncertainty. But the circumstances under which FL or stochastic methods should be used are shrouded in disagreement, because the areas of application of statistical and FL methods are overlapping with differences in opinion as to when which method should be used. Lacking are practically relevant case studies comparing these two methods. This work compares stochastic and FL methods for the assessment of spare capacity on the example of pharmaceutical high purity water (HPW) utility systems. The goal of this study was to find the most appropriate method modelling uncertainty in industrial scale HPW systems. The results provide evidence which suggests that stochastic methods are superior to the methods of FL in simulating uncertainty in chemical plant utilities including HPW systems in typical cases whereby extreme events, for example peaks in demand, or day-to-day variation rather than average values are of interest. The average production output or other statistical measures may, for instance, be of interest in the assessment of workshops. Furthermore the results indicate that the stochastic model should be used only if found necessary by a deterministic simulation. Consequently, this thesis concludes that either deterministic or stochastic methods should be used to simulate uncertainty in chemical plant utility systems and by extension some process system because extreme events or the modelling of day-to-day variation are important in capacity extension projects. Other reasons supporting the suggestion that stochastic HPW models are preferred to FL HPW models include: 1. The computer code for stochastic models is typically less complex than a FL models, thus reducing code maintenance and validation issues. 2. In many respects FL models are similar to deterministic models. Thus the need for a FL model over a deterministic model is questionable in the case of industrial scale HPW systems as presented here (as well as other similar systems) since the latter requires simpler models. 3. A FL model may be difficult to "sell" to an end-user as its results represent "approximate reasoning" a definition of which is, however, lacking. 4. Stochastic models may be applied with some relatively minor modifications on other systems, whereas FL models may not. For instance, the stochastic HPW system could be used to model municipal drinking water systems, whereas the FL HPW model should or could not be used on such systems. This is because the FL and stochastic model philosophies of a HPW system are fundamentally different. The stochastic model sees schedule and volume uncertainties as random phenomena described by statistical distributions based on either estimated or historical data. The FL model, on the other hand, simulates schedule uncertainties based on estimated operator behaviour e.g. tiredness of the operators and their working schedule. But in a municipal drinking water distribution system the notion of "operator" breaks down. 5. Stochastic methods can account for uncertainties that are difficult to model with FL. The FL HPW system model does not account for dispensed volume uncertainty, as there appears to be no reasonable method to account for it with FL whereas the stochastic model includes volume uncertainty.

Azione destabilizzante e impegno politico. Le figure femminili tra il giallo e il nero Italiani dal 1980 a oggi

My thesis analyses female figures in Italian crime fiction since 1980, from narratological, sociological and gender-studies perspectives. It considers the narrative structure of the giallo and the noir, taking into account the difficulties, particularly in Italy, of establishing what noir fiction is and if/how it is possible to frame it in a specific narrative scheme. This discourse connects to the extraordinary success of Italian giallo and noir fiction over the past fifteen-twenty years. In this scenario, I examine the place of female writers in relation to this phenomenon, especially since the 1980s: in terms of the level of visibility/acceptance of their work, in a narrative space traditionally considered as a male territory, and with regard to their writings, which introduce different narrative perspectives. Specifically, I consider selected texts by leading female Italian writers, in which female elements (writers/characters) become destabilizing factor both on the narrative level, by undermining the schemes of ‘formulaic’ fiction, and on the political one, through their implicit potential (as women) for disrupting the rigid models inherited from processes of social conditioning and from political structures. In terms of gender identities, such texts offer scope to question conventional social constructions of the subject: by empowering the female narrative voice and by embodying it in characters (investigators/killers) traditionally personified by male figures. These texts offer themselves as a critical space where, potentially, readers can rethink static gendered relationships and stereotypical symbolical categories.

Natural streamflow regime alterations: Damming of the Piave river basin (Italy)

A novel approach is proposed to estimate the natural streamflow regime of a river and to assess the extent of the alterations induced by dam operation related to anthropogenic (e.g., agricultural, hydropower) water uses in engineered river basins. The method consists in the comparison between the seasonal probability density function (pdf) of observed streamflows and the purportedly natural streamflow pdf obtained by a recently proposed and validated probabilistic model. The model employs a minimum of landscape and climate parameters and unequivocally separates the effects of anthropogenic regulations from those produced by hydroclimatic fluctuations. The approach is applied to evaluate the extent of the alterations of intra-annual streamflow variability in a highly engineered alpine catchment of north-eastern Italy, the Piave river. Streamflows observed downstream of the regulation devices in the Piave catchment are found to exhibit smaller means/modes, larger coefficients of variation, and more pronounced peaks than the flows that would be observed in the absence of anthropogenic regulation, suggesting that the anthropogenic disturbance leads to remarkable reductions of river flows, with an increase of the streamflow variability and of the frequency of preferential states far from the mean. Some structural limitations of management approaches based on minimum streamflow requirements (widely used to guide water policies) as opposed to criteria based on whole distributions are also discussed. Copyright © 2010 by the American Geophysical Union.

Laparoscopic Appendectomy in Italy: An Appraisal of 26,863 Cases

Objective: To evaluate the practice of laparoscopic appendectomy (LA) in Italy. Methods: On behalf of the Italian Society of Young Surgeons (SPIGC), an audit of LA was carried out through a written questionnaire sent to 800 institutions in Italy. The questions concerned the diffusion of laparoscopic surgery and LA over the period 1990 through 2001, surgery-related morbidity and mortality rates, indications for LA, the diagnostic algorithm adopted prior to surgery, and use of LA among young surgeons (<40 years). Results: A total of 182 institutions (22.7%) participated in the current audit, and accounted for a total number of 26863 LA. Laparoscopic surgery is performed in 173 (95%) institutions, with 144 (83.2%) routinely performing LA. The mean interval from introduction of laparoscopic surgery to inception of LA was 3.4 ± 2.5 years. There was an emergent basis for 8809 (32.8%) LA procedures (<6 hours of admission); 10314 (38.4%) procedures were performed on an urgent basis (<24 hours of admission); while 7740 (28.8%) procedures were elective. The conversion rate was 2.1% (561 cases) and was due to intraoperative complications in 197 cases (35.1%). Intraoperative complications ranged as high as 0.32%, while postoperative complications were reported in 1.2% of successfully completed LA. The mean hospital stay for successfully completed LA was 2.5 ± 1.05 days. The highest rate of intraoperative complications was reported as occurring during the learning curve phase of their experience (in their first 10 procedures) by 39.7% of the surgeons. LA was indicated for every case of suspected acute appendiceal disease by 51.8% of surgeons, and 44.8% order abdominal ultrasound (US) prior to surgery. A gynecologic counseling is deemed necessary only by 34.5% surgeons, while an abdominal CT scan is required only by 1.5%. The procedure is completed laparoscopically in the absence of gross appendiceal inflammation by 83%; 79.8% try to complete the procedure laparoscopically in the presence of concomitant disease; while 10.4% convert to open surgery in cases of suspected malignancy. Of responding surgeons aged under 40, 76.3% can perform LA, compared to 47.3% surgeons of all age categories. Conclusions: The low response rate of the present survey does not allow us to assess the diffusion of LA in Italy, but rather to appraise its practice in centers routinely performing laparoscopic surgery. In the hands of experienced surgeons, LA has morbidity rates comparable to those of international series. The higher diagnostic yield of laparoscopy makes it an invaluable tool in the management algorithm of women of childbearing age; its advantages in the presence of severe peritonitis are less clear-cut. Surgeons remain the main limiting factor preventing a wider diffusion of LA in our country, since only 47.3% of surgeons from the audited institutions can perform LA on a routine basis.

Evaluation de DI-fusion: Le dépôt officiel de l'ULB

info:eu-repo/semantics/published