The stratigraphic record of the quaternary sea level fluctuations and the impact of the post-glacial sea level rise (Termination I) in the Adriatic basin (Mediterranean sea)

The modern stratigraphy of clastic continental margins is the result of the interaction between several geological processes acting on different time scales, among which sea level oscillations, sediment supply fluctuations and local tectonics are the main mechanisms. During the past three years my PhD was focused on understanding the impact of each of these process in the deposition of the central and northern Adriatic sedimentary successions, with the aim of reconstructing and quantifying the Late Quaternary eustatic fluctuations. In the last few decades, several Authors tried to quantify past eustatic fluctuations through the analysis of direct sea level indicators, among which drowned barrier-island deposits or coral reefs, or indirect methods, such as Oxygen isotope ratios (δ18O) or modeling simulations. Sea level curves, obtained from direct sea level indicators, record a composite signal, formed by the contribution of the global eustatic change and regional factors, as tectonic processes or glacial-isostatic rebound effects: the eustatic signal has to be obtained by removing the contribution of these other mechanisms. To obtain the most realistic sea level reconstructions it is important to quantify the tectonic regime of the central Adriatic margin. This result has been achieved integrating a numerical approach with the analysis of high-resolution seismic profiles. In detail, the subsidence trend obtained from the geohistory analysis and the backstripping of the borehole PRAD1.2 (the borehole PRAD1.2 is a 71 m continuous borehole drilled in -185 m of water depth, south of the Mid Adriatic Deep - MAD - during the European Project PROMESS 1, Profile Across Mediterranean Sedimentary Systems, Part 1), has been confirmed by the analysis of lowstand paleoshorelines and by benthic foraminifera associations investigated through the borehole. This work showed an evolution from inner-shelf environment, during Marine Isotopic Stage (MIS) 10, to upper-slope conditions, during MIS 2. Once the tectonic regime of the central Adriatic margin has been constrained, it is possible to investigate the impact of sea level and sediment supply fluctuations on the deposition of the Late Pleistocene-Holocene transgressive deposits. The Adriatic transgressive record (TST - Transgressive Systems Tract) is formed by three correlative sedimentary bodies, deposited in less then 14 kyr since the Last Glacial Maximum (LGM); in particular: along the central Adriatic shelf and in the adjacent slope basin the TST is formed by marine units, while along the northern Adriatic shelf the TST is represented by costal deposits in a backstepping configuration. The central Adriatic margin, characterized by a thick transgressive sedimentary succession, is the ideal site to investigate the impact of late Pleistocene climatic and eustatic fluctuations, among which Meltwater Pulses 1A and 1B and the Younger Dryas cold event. The central Adriatic TST is formed by a tripartite deposit bounded by two regional unconformities. In particular, the middle TST unit includes two prograding wedges, deposited in the interval between the two Meltwater Pulse events, as highlighted by several 14C age estimates, and likely recorded the Younger Dryas cold interval. Modeling simulations, obtained with the two coupled models HydroTrend 3.0 and 2D-Sedflux 1.0C (developed by the Community Surface Dynamics Modeling System - CSDMS), integrated by the analysis of high resolution seismic profiles and core samples, indicate that: 1 - the prograding middle TST unit, deposited during the Younger Dryas, was formed as a consequence of an increase in sediment flux, likely connected to a decline in vegetation cover in the catchment area due to the establishment of sub glacial arid conditions; 2 - the two-stage prograding geometry was the consequence of a sea level still-stand (or possibly a fall) during the Younger Dryas event. The northern Adriatic margin, characterized by a broad and gentle shelf (350 km wide with a low angle plunge of 0.02° to the SE), is the ideal site to quantify the timing of each steps of the post LGM sea level rise. The modern shelf is characterized by sandy deposits of barrier-island systems in a backstepping configuration, showing younger ages at progressively shallower depths, which recorded the step-wise nature of the last sea level rise. The age-depth model, obtained by dated samples of basal peat layers, is in good agreement with previous published sea level curves, and highlights the post-glacial eustatic trend. The interval corresponding to the Younger Dyas cold reversal, instead, is more complex: two coeval coastal deposits characterize the northern Adriatic shelf at very different water depths. Several explanations and different models can be attempted to explain this conundrum, but the problem remains still unsolved.

L'a(rche)tipico Brian O'Nolan. Comico e riso dalla tradizione al post-

This study aims at analysing Brian O'Nolans literary production in the light of a reconsideration of the role played by his two most famous pseudonyms ,Flann Brien and Myles na Gopaleen, behind which he was active both as a novelist and as a journalist. We tried to establish a new kind of relationship between them and their empirical author following recent cultural and scientific surveys in the field of Humour Studies, Psychology, and Sociology: taking as a starting point the appreciation of the comic attitude in nature and in cultural history, we progressed through a short history of laughter and derision, followed by an overview on humour theories. After having established such a frame, we considered an integration of scientific studies in the field of laughter and humour as a base for our study scheme, in order to come to a definition of the comic author as a recognised, powerful and authoritative social figure who acts as a critic of conventions. The history of laughter and comic we briefly summarized, based on the one related by the French scholar Georges Minois in his work (Minois 2004), has been taken into account in the view that humorous attitude is one of man’s characteristic traits always present and witnessed throughout the ages, though subject in most cases to repression by cultural and political conservative power. This sort of Super-Ego notwithstanding, or perhaps because of that, comic impulse proved irreducible exactly in its influence on the current cultural debates. Basing mainly on Robert R. Provine’s (Provine 2001), Fabio Ceccarelli’s (Ceccarelli 1988), Arthur Koestler’s (Koestler 1975) and Peter L. Berger’s (Berger 1995) scientific essays on the actual occurrence of laughter and smile in complex social situations, we underlined the many evidences for how the use of comic, humour and wit (in a Freudian sense) could be best comprehended if seen as a common mind process designed for the improvement of knowledge, in which we traced a strict relation with the play-element the Dutch historian Huizinga highlighted in his famous essay, Homo Ludens (Huizinga 1955). We considered comic and humour/wit as different sides of the same coin, and showed how the demonstrations scientists provided on this particular subject are not conclusive, given that the mental processes could not still be irrefutably shown to be separated as regards graduations in comic expression and reception: in fact, different outputs in expressions might lead back to one and the same production process, following the general ‘Economy Rule’ of evolution; man is the only animal who lies, meaning with this that one feeling is not necessarily biuniquely associated with one and the same outward display, so human expressions are not validation proofs for feelings. Considering societies, we found that in nature they are all organized in more or less the same way, that is, in élites who govern over a community who, in turn, recognizes them as legitimate delegates for that task; we inferred from this the epistemological possibility for the existence of an added ruling figure alongside those political and religious: this figure being the comic, who is the person in charge of expressing true feelings towards given subjects of contention. Any community owns one, and his very peculiar status is validated by the fact that his place is within the community, living in it and speaking to it, but at the same time is outside it in the sense that his action focuses mainly on shedding light on ideas and objects placed out-side the boundaries of social convention: taboos, fears, sacred objects and finally culture are the favourite targets of the comic person’s arrow. This is the reason for the word a(rche)typical as applied to the comic figure in society: atypical in a sense, because unconventional and disrespectful of traditions, critical and never at ease with unblinkered respect of canons; archetypical, because the “village fool”, buffoon, jester or anyone in any kind of society who plays such roles, is an archetype in the Jungian sense, i.e. a personification of an irreducible side of human nature that everybody instinctively knows: a beginner of a tradition, the perfect type, what is most conventional of all and therefore the exact opposite of an atypical. There is an intrinsic necessity, we think, of such figures in societies, just like politicians and priests, who should play an elitist role in order to guide and rule not for their own benefit but for the good of the community. We are not naïve and do know that actual owners of power always tend to keep it indefinitely: the ‘social comic’ as a role of power has nonetheless the distinctive feature of being the only job whose tension is not towards stability. It has got in itself the rewarding permission of contradiction, for the very reason we exposed before that the comic must cast an eye both inside and outside society and his vision may be perforce not consistent, then it is satisfactory for the popularity that gives amongst readers and audience. Finally, the difference between governors, priests and comic figures is the seriousness of the first two (fundamentally monologic) and the merry contradiction of the third (essentially dialogic). MPs, mayors, bishops and pastors should always console, comfort and soothe popular mood in respect of the public convention; the comic has the opposite task of provoking, urging and irritating, accomplishing at the same time a sort of control of the soothing powers of society, keepers of the righteousness. In this view, the comic person assumes a paramount importance in the counterbalancing of power administration, whether in form of acting in public places or in written pieces which could circulate for private reading. At this point comes into question our Irish writer Brian O'Nolan(1911-1966), real name that stood behind the more famous masks of Flann O'Brien, novelist, author of At Swim-Two-Birds (1939), The Hard Life (1961), The Dalkey Archive (1964) and, posthumously, The Third Policeman (1967); and of Myles na Gopaleen, journalist, keeper for more than 25 years of the Cruiskeen Lawn column on The Irish Times (1940-1966), and author of the famous book-parody in Irish An Béal Bocht (1941), later translated in English as The Poor Mouth (1973). Brian O'Nolan, professional senior civil servant of the Republic, has never seen recognized his authorship in literary studies, since all of them concentrated on his alter egos Flann, Myles and some others he used for minor contributions. So far as we are concerned, we think this is the first study which places the real name in the title, this way acknowledging him an unity of intents that no-one before did. And this choice in titling is not a mere mark of distinction for the sake of it, but also a wilful sign of how his opus should now be reconsidered. In effect, the aim of this study is exactly that of demonstrating how the empirical author Brian O'Nolan was the real Deus in machina, the master of puppets who skilfully directed all of his identities in planned directions, so as to completely fulfil the role of the comic figure we explained before. Flann O'Brien and Myles na Gopaleen were personae and not persons, but the impression one gets from the critical studies on them is the exact opposite. Literary consideration, that came only after O'Nolans death, began with Anne Clissmann’s work, Flann O'Brien: A Critical Introduction to His Writings (Clissmann 1975), while the most recent book is Keith Donohue’s The Irish Anatomist: A Study of Flann O'Brien (Donohue 2002); passing through M.Keith Booker’s Flann O'Brien, Bakhtin and Menippean Satire (Booker 1995), Keith Hopper’s Flann O'Brien: A Portrait of the Artist as a Young Post-Modernist (Hopper 1995) and Monique Gallagher’s Flann O'Brien, Myles et les autres (Gallagher 1998). There have also been a couple of biographies, which incidentally somehow try to explain critical points his literary production, while many critical studies do the same on the opposite side, trying to found critical points of view on the author’s restless life and habits. At this stage, we attempted to merge into O'Nolan's corpus the journalistic articles he wrote, more than 4,200, for roughly two million words in the 26-year-old running of the column. To justify this, we appealed to several considerations about the figure O'Nolan used as writer: Myles na Gopaleen (later simplified in na Gopaleen), who was the equivalent of the street artist or storyteller, speaking to his imaginary public and trying to involve it in his stories, quarrels and debates of all kinds. First of all, he relied much on language for the reactions he would obtain, playing on, and with, words so as to ironically unmask untrue relationships between words and things. Secondly, he pushed to the limit the convention of addressing to spectators and listeners usually employed in live performing, stretching its role in the written discourse to come to a greater effect of involvement of readers. Lastly, he profited much from what we labelled his “specific weight”, i.e. the potential influence in society given by his recognised authority in determined matters, a position from which he could launch deeper attacks on conventional beliefs, so complying with the duty of a comic we hypothesised before: that of criticising society even in threat of losing the benefits the post guarantees. That seemingly masochistic tendency has its rationale. Every representative has many privileges on the assumption that he, or she, has great responsibilities in administrating. The higher those responsibilities are, the higher is the reward but also the severer is the punishment for the misfits done while in charge. But we all know that not everybody accepts the rules and many try to use their power for their personal benefit and do not want to undergo law’s penalties. The comic, showing in this case more civic sense than others, helped very much in this by the non-accessibility to the use of public force, finds in the role of the scapegoat the right accomplishment of his task, accepting the punishment when his breaking of the conventions is too stark to be forgiven. As Ceccarelli demonstrated, the role of the object of laughter (comic, ridicule) has its very own positive side: there is freedom of expression for the person, and at the same time integration in the society, even though at low levels. Then the banishment of a ‘social’ comic can never get to total extirpation from society, revealing how the scope of the comic lies on an entirely fictional layer, bearing no relation with facts, nor real consequences in terms of physical health. Myles na Gopaleen, mastering these three characteristics we postulated in the highest way, can be considered an author worth noting; and the oeuvre he wrote, the whole collection of Cruiskeen Lawn articles, is rightfully a novel because respects the canons of it especially regarding the authorial figure and his relationship with the readers. In addition, his work can be studied even if we cannot conduct our research on the whole of it, this proceeding being justified exactly because of the resemblances to the real figure of the storyteller: its ‘chapters’ —the daily articles— had a format that even the distracted reader could follow, even one who did not read each and every article before. So we can critically consider also a good part of them, as collected in the seven volumes published so far, with the addition of some others outside the collections, because completeness in this case is not at all a guarantee of a better precision in the assessment; on the contrary: examination of the totality of articles might let us consider him as a person and not a persona. Once cleared these points, we proceeded further in considering tout court the works of Brian O'Nolan as the works of a unique author, rather than complicating the references with many names which are none other than well-wrought sides of the same personality. By putting O'Nolan as the correct object of our research, empirical author of the works of the personae Flann O'Brien and Myles na Gopaleen, there comes out a clearer literary landscape: the comic author Brian O'Nolan, self-conscious of his paramount role in society as both a guide and a scourge, in a word as an a(rche)typical, intentionally chose to differentiate his personalities so as to create different perspectives in different fields of knowledge by using, in addition, different means of communication: novels and journalism. We finally compared the newly assessed author Brian O'Nolan with other great Irish comic writers in English, such as James Joyce (the one everybody named as the master in the field), Samuel Beckett, and Jonathan Swift. This comparison showed once more how O'Nolan is in no way inferior to these authors who, greatly celebrated by critics, have nonetheless failed to achieve that great public recognition O’Nolan received alias Myles, awarded by the daily audience he reached and influenced with his Cruiskeen Lawn column. For this reason, we believe him to be representative of the comic figure’s function as a social regulator and as a builder of solidarity, such as that Raymond Williams spoke of in his work (Williams 1982), with in mind the aim of building a ‘culture in common’. There is no way for a ‘culture in common’ to be acquired if we do not accept the fact that even the most functional society rests on conventions, and in a world more and more ‘connected’ we need someone to help everybody negotiate with different cultures and persons. The comic gives us a worldly perspective which is at the same time comfortable and distressing but in the end not harmful as the one furnished by politicians could be: he lets us peep into parallel worlds without moving too far from our armchair and, as a consequence, is the one who does his best for the improvement of our understanding of things.

The engagement of yugoslav technical cooperation experts in post-colonial Algeria (1962-1990). A global microhistory of east-south relations

The venture of socialist Eastern Europe in assisting the development efforts of the post-colonial countries opened up official migratory channels to the Global South for a specific labour group engaged under international technical cooperation programmes. By taking post-colonial Algeria as a space of East-South interactions and intense inter-socialist competition, the thesis studies labour mobility from socialist Yugoslavia of a heterogeneous group labelled “technical cooperation experts” in the period from 1962 to 1990. While CMEA members dispatched to the country personnel in great numbers, after 1965, Yugoslavia failed to do so. Tracing them beyond the institutional level, the thesis aims at detecting and exposing factors which inhibited the attempts to increase the presence of Yugoslav technical experts in Algeria. It argues that instead of building an alternative, solidarity-based aid model, Yugoslav technical cooperation with the developing countries was reduced to mediation in the employment of highly-skilled labour abroad. The cooperation scheme, which differed from one of its Eastern European counterparts, manifested in the employment and legal status as well as everyday life and work experiences of Yugoslav citizens. Relying on the methodological approach of global microhistory, which strongly favours the micro-historical analysis of primary sources in studying global processes, the thesis provides a more comprehensive and nuanced understanding of Yugoslav globalization endeavours. By shifting the focus to the experiences of ordinary people who were under the strong influence of globalization forces of the Cold War era, the thesis adds a “human” dimension to the history of East-South relations.

Tectonics of the wedge-top Epiligurian basins and implications for the syn-to-post orogenic evolution of the Northern Apennines fold-and-thrust belt (Italy)

This thesis has the aim to give an overview about the tectonic history of the Epiligurian units, which crop out in the axial portion of the Northern Apennines fold-and-thrust belt, from a structural and thermal point of view, through a multiscalar and multitecnique approach. I focused on a key example of Epiligurian wedge-top basin, (Marzabotto Basin) proceeding from macro-to-microscale approach. The study started from a remote sensing analysis of the lineaments and morphostructures which affected the study area to obtain the regional faulting pattern and an overview about the main tectonic structures, used as basis for the structural investigation at the mesoscale. On the basis of this, it was possible to reconstruct the succession of tectonic events that affected the Marzabotto Basin, consisting in: i) two sets of thrusts indicating a NE-SW and NW-SE shortening of the sedimentary succession; ii) NE-SW-left lateral transtensional faults related to a strike-slip tectonic phase; iii) three main sets of extensional structures which cut and displace the previous thrusts. Normal faults are related to the post-orogenic evolution and have been dated with U-Th method, getting an age of Middle-Late Pleistocene. From a thermal point of view, apatite fission-tracks and (U-Th)/He analyses of detrital minerals and thermal modelling on the middle-upper Eocene siliciclastic deposits allowed me to better constrain the local exhumation history and correlate it with the large-scale tectonic evolution of the Northern Apennines. In particular, the Marzabotto Basin experienced a complex burial-exhumation history, consisting in two cooling cooling phases related to the growth of the Northern Apennines belt (Oligo-Miocene in age) and a later cooling which tracks the accretion in the orogenic wedge concomitant with rollback-driven extension (late Miocene-Pliocene in age). In conclusion it is possible to affirm that the study shed new light on poorly constrained elements of fold-and-thrust belt.

Expression of the repressor element-1 silencing transcription factor (REST) is regulated by IGF-I and PKC in human neuroblastoma cells

The repressor element 1-silencing transcription factor (REST) was first identified as a protein that binds to a 21-bp DNA sequence element (known as repressor element 1 (RE1)) resulting in transcriptional repression of the neural-specific genes [Chong et al., 1995; Schoenherr and Anderson, 1995]. The original proposed role for REST was that of a factor responsible for restricting neuronal gene expression to the nervous system by silencing expression of these genes in non-neuronal cells. Although it was initially thought to repress neuronal genes in non-neuronal cells, the role of REST is complex and tissue dependent. In this study I investigated any role played by REST in the induction and patterning of differentiation of SH-SY5Y human neuroblastoma cells exposed to IGF-I. and phorbol 12- myristate 13-acetate (PMA) To down-regulate REST expression we developed an antisense (AS) strategy based on the use of phosphorothioate oligonucleotides (ODNs). In order to evaluate REST mRNA levels, we developed a real-time PCR technique and REST protein levels were evaluated by western blotting. Results showed that nuclear REST is increased in SH-SY5Y neuroblastoma cells cultured in SFM and exposed to IGF-I for 2-days and it then declines in 5-day-treated cells concomitant with a progressive neurite extension. Also the phorbol ester PMA was able to increase nuclear REST levels after 3-days treatment concomitant to neuronal differentiation of neuroblastoma cells, whereas, at later stages, it is down-regulated. Supporting these data, the exposure to PKC inhibitors (GF10923X and Gö6976) and PMA (16nM) reverted the effects observed with PMA alone. REST levels were related to morphological differentiation, expression of growth coneassociated protein 43 (GAP-43; a gene not regulated by REST) and of synapsin I and βIII tubulin (genes regulated by REST), proteins involved in the early stage of neuronal development. We observed that differentiation of SH-SY5Y cells by IGF-I and PMA was accompanied by a significant increase of these neuronal markers, an effect that was concomitant with REST decrease. In order to relate the decreased REST expression with a progressive neurite extension, I investigated any possible involvement of the ubiquitin–proteasome system (UPS), a multienzymatic pathway which degrades polyubiquinated soluble cytoplasmic proteins [Pickart and Cohen, 2004]. For this purpose, SH-SY5Y cells are concomitantly exposed to PMA and the proteasome inhibitor MG132. In SH-SY5Y exposed to PMA and MG 132, we observed an inverse pattern of expression of synapsin I and β- tubulin III, two neuronal differentiation markers regulated by REST. Their cytoplasmic levels are reduced when compared to cells exposed to PMA alone, as a consequence of the increase of REST expression by proteasome inhibitor. The majority of proteasome substrates identified to date are marked for degradation by polyubiquitinylation; however, exceptions to this principle, are well documented [Hoyt and Coffino, 2004]. Interestingly, REST degradation seems to be completely ubiquitin-independent. The expression pattern of REST could be consistent with the theory that, during early neuronal differentiation induced by IGF-I and PKC, it may help to repress the expression of several genes not yet required by the differentiation program and then it declines later. Interestingly, the observation that REST expression is progressively reduced in parallel with cell proliferation seems to indicate that the role of this transcription factor could also be related to cell survival or to counteract apotosis events [Lawinger et al., 2000] although, as shown by AS-ODN experiments, it does not seem to be directly involved in cell proliferation. Therefore, the decline of REST expression is a comparatively later event during maturation of neuroroblasts in vitro. Thus, we propose that REST is regulated by growth factors, like IGF-I, and PKC activators in a time-dependent manner: it is elevated during early steps of neural induction and could contribute to down-regulate genes not yet required by the differentiation program while it declines later for the acquisition of neural phenotypes, concomitantly with a progressive neurite extension. This later decline is regulated by the proteasome system activation in an ubiquitin-indipendent way and adds more evidences to the hypothesis that REST down-regulation contributes to differentiation and arrest of proliferation of neuroblastoma cells. Finally, the glycosylation pattern of the REST protein was analysed, moving from the observation that the molecular weight calculated on REST sequence is about 116 kDa but using western blotting this transcription factor appears to have distinct apparent molecular weight (see Table 1.1): this difference could be explained by post-translational modifications of the proteins, like glycosylation. In fact recently, several studies underlined the importance of O-glycosylation in modulating transcriptional silencing, protein phosphorylation, protein degradation by proteasome and protein–protein interactions [Julenius et al., 2005; Zachara and Hart, 2006]. Deglycosilating analysis showed that REST protein in SH-SY5Y and HEK293 cells is Oglycosylated and not N-glycosylated. Moreover, using several combination of deglycosilating enzymes it is possible to hypothesize the presence of Gal-β(1-3)-GalNAc residues on the endogenous REST, while β(1-4)-linked galactose residues may be present on recombinant REST protein expressed in HEK293 cells. However, the O-glycosylation process produces an immense multiplicity of chemical structures and monosaccharides must be sequentially hydrolyzed by a series of exoglycosidase. Further experiments are needed to characterize all the post-translational modification of the transcription factor REST.

MCAO for Extremely Large Telescopes: the cases of LBT and E-ELT

Several MCAO systems are under study to improve the angular resolution of the current and of the future generation large ground-based telescopes (diameters in the 8-40 m range). The subject of this PhD Thesis is embedded in this context. Two MCAO systems, in dierent realization phases, are addressed in this Thesis: NIRVANA, the 'double' MCAO system designed for one of the interferometric instruments of LBT, is in the integration and testing phase; MAORY, the future E-ELT MCAO module, is under preliminary study. These two systems takle the sky coverage problem in two dierent ways. The layer oriented approach of NIRVANA, coupled with multi-pyramids wavefront sensors, takes advantage of the optical co-addition of the signal coming from up to 12 NGS in a annular 2' to 6' technical FoV and up to 8 in the central 2' FoV. Summing the light coming from many natural sources permits to increase the limiting magnitude of the single NGS and to improve considerably the sky coverage. One of the two Wavefront Sensors for the mid- high altitude atmosphere analysis has been integrated and tested as a stand- alone unit in the laboratory at INAF-Osservatorio Astronomico di Bologna and afterwards delivered to the MPIA laboratories in Heidelberg, where was integrated and aligned to the post-focal optical relay of one LINC-NIRVANA arm. A number of tests were performed in order to characterize and optimize the system functionalities and performance. A report about this work is presented in Chapter 2. In the MAORY case, to ensure correction uniformity and sky coverage, the LGS-based approach is the current baseline. However, since the Sodium layer is approximately 10 km thick, the articial reference source looks elongated, especially when observed from the edge of a large aperture. On a 30-40 m class telescope, for instance, the maximum elongation varies between few arcsec and 10 arcsec, depending on the actual telescope diameter, on the Sodium layer properties and on the laser launcher position. The centroiding error in a Shack-Hartmann WFS increases proportionally to the elongation (in a photon noise dominated regime), strongly limiting the performance. To compensate for this effect a straightforward solution is to increase the laser power, i.e. to increase the number of detected photons per subaperture. The scope of Chapter 3 is twofold: an analysis of the performance of three dierent algorithms (Weighted Center of Gravity, Correlation and Quad-cell) for the instantaneous LGS image position measurement in presence of elongated spots and the determination of the required number of photons to achieve a certain average wavefront error over the telescope aperture. An alternative optical solution to the spot elongation problem is proposed in Section 3.4. Starting from the considerations presented in Chapter 3, a first order analysis of the LGS WFS for MAORY (number of subapertures, number of detected photons per subaperture, RON, focal plane sampling, subaperture FoV) is the subject of Chapter 4. An LGS WFS laboratory prototype was designed to reproduce the relevant aspects of an LGS SH WFS for the E-ELT and to evaluate the performance of different centroid algorithms in presence of elongated spots as investigated numerically and analytically in Chapter 3. This prototype permits to simulate realistic Sodium proles. A full testing plan for the prototype is set in Chapter 4.

Investigating the role of single point mutations in the human proteome: a computational study

In the post genomic era with the massive production of biological data the understanding of factors affecting protein stability is one of the most important and challenging tasks for highlighting the role of mutations in relation to human maladies. The problem is at the basis of what is referred to as molecular medicine with the underlying idea that pathologies can be detailed at a molecular level. To this purpose scientific efforts focus on characterising mutations that hamper protein functions and by these affect biological processes at the basis of cell physiology. New techniques have been developed with the aim of detailing single nucleotide polymorphisms (SNPs) at large in all the human chromosomes and by this information in specific databases are exponentially increasing. Eventually mutations that can be found at the DNA level, when occurring in transcribed regions may then lead to mutated proteins and this can be a serious medical problem, largely affecting the phenotype. Bioinformatics tools are urgently needed to cope with the flood of genomic data stored in database and in order to analyse the role of SNPs at the protein level. In principle several experimental and theoretical observations are suggesting that protein stability in the solvent-protein space is responsible of the correct protein functioning. Then mutations that are found disease related during DNA analysis are often assumed to perturb protein stability as well. However so far no extensive analysis at the proteome level has investigated whether this is the case. Also computationally methods have been developed to infer whether a mutation is disease related and independently whether it affects protein stability. Therefore whether the perturbation of protein stability is related to what it is routinely referred to as a disease is still a big question mark. In this work we have tried for the first time to explore the relation among mutations at the protein level and their relevance to diseases with a large-scale computational study of the data from different databases. To this aim in the first part of the thesis for each mutation type we have derived two probabilistic indices (for 141 out of 150 possible SNPs): the perturbing index (Pp), which indicates the probability that a given mutation effects protein stability considering all the “in vitro” thermodynamic data available and the disease index (Pd), which indicates the probability of a mutation to be disease related, given all the mutations that have been clinically associated so far. We find with a robust statistics that the two indexes correlate with the exception of all the mutations that are somatic cancer related. By this each mutation of the 150 can be coded by two values that allow a direct comparison with data base information. Furthermore we also implement computational methods that starting from the protein structure is suited to predict the effect of a mutation on protein stability and find that overpasses a set of other predictors performing the same task. The predictor is based on support vector machines and takes as input protein tertiary structures. We show that the predicted data well correlate with the data from the databases. All our efforts therefore add to the SNP annotation process and more importantly found the relationship among protein stability perturbation and the human variome leading to the diseasome.

Dietary strategies to minimize the detrimental impact of weaning on gut morphology, physiology and microbiota of piglets

Weaning is a crucial period in the management of piglets. In modern piggeries economic interest make weaning age decrease more and more and the detrimental consequences of weaning have as much importance as earlier the weaning occurs. The risk of development of post-weaning diarrhea (PWD) in piglets is high and PWD is the cause of serious economic losses in pig herds. In the past the supplementation of the feed given after weaning with growth promoters antibiotics, in order to keep PWD under control, used to be a common practice, but their usage has been banned in EU since 2006. This measure led to the investigation of alternative suitable feed supplements that would be reasonably efficient in protecting and sustaining animal health and performance. Aim of this thesis was to evaluate the effect of some different alternatives to growth-promoters antibiotics on weaning piglets and to assess if some of them could be considered as valuables options to replace auxinic in animal feeding. The study is composed by four experimental trials. The first one aims to identify mechanisms involved in the auxinic effects of antibiotics in the diets; the following three evaluate the addition butyric acid, tryptophan, and nitrate as alternative to in-feed antimicrobials. Although some results are controversial, it appears from the data presented that the alternatives to in-feed antibiotics considered may exert positive effects on some zootechnical and health parameters on piglet in the post-weaning period. Anyway, the mechanism of action and the interaction with microbiota of such additives should be investigated inside out because many effects remains poorly understood.

Risk factors for postoperative delirium in the elderly

Background: Delirium is defined as an acute disorder of attention and cognition. Delirium is common in hospitalized elderly patient and is associated with increased morbidity, length of stay and patient care costs. Although Delirium can develop at any time during hospitalization, it typically presents early in the post-operative period (Post-Operative Delirium, POD) in the surgery context. The molecular mechanism and possible genetics basis of POD onset are not known, as well as all the risk factors are not completely defined. Our hypothesis is that genetic risk factor involving the inflammatory response could have possible effects on the immunoneuroendocrine system. Moreover, our previous data (inflamm-aging) suggest that aging is associated with an increase of inflammatory status, favouring age-related diseases such as neurodegenerative diseases, frailty, depression among other. Some pro-inflammatory or anti-inflammatory cytokines, seem to play a crucial role in increasing the inflammatory status and in the communication and regulation of immunoneuroendocrine system. Objective: this study evaluated the incidence of POD in elderly patients undergoing general surgery, clinical/physical and psychological risk factors of POD insurgency and investigated inflammatory and genetic risk factors. Moreover, this study evaluated the consequence of POD in terms of institutionalization, development of permanent cognitive dysfunction or dementia and mortality Methods: patients aged over 65 admitted for surgery at the Urgency Unit of S.Orsola-Malpighi Hospital were eligible for this case–control study. Risk factors significantly associated with POD in univariate analysis were entered into multivariate analysis to establish those independently associated with POD. Preoperative plasma level of 9 inflammatory markers were measured in 42 control subjects and 43 subjects who developed POD. Functional polymorphisms of IL-1 α , IL-2, IL-6, IL-8, IL-10 and TNF-alpha cytokine genes were determined in 176 control subjects and 27 POD subjects. Results: A total of 351 patients were enrolled in the study. The incidence of POD was 13•2 %. Independent variables associated with POD were: age, co-morbidity, preoperative cognitive impairment, glucose abnormalities. Median length of hospital stay was 21 days for patients with POD versus 8 days for control patients (P < 0•001). The hospital mortality rate was 19 and 8•4 % respectively (P = 0•021) and mortality rate after 1 year was also higher in POD (P= 0.0001). The baseline of IL-6 concentration was higher in POD patients than patients without POD, whereas IL-2 was lower in POD patients compared to patients without POD. In a multivariate analysis only IL-6 remained associated with POD. Moreover IL-6, IL-8 and IL-2 are associated with co-morbidity, intra-hospital mortality, compromised functional status and emergency admission. No significant differences in genotype distribution were found between POD subjects and controls for any SNP analyzed in this study. Conclusion: In this study we found older age, comorbidity, cognitive impairment, glucose abnormalities and baseline of IL-6 as independent risk factors for the development of POD. IL-6 could be proposed as marker of a trait that is associated with an increased risk of delirium; i.e. raised premorbid IL-6 level predict for the development of delirium.

Innovative Strategies for the Synthesis of Biologically Active Small Molecules

The post genomic era, set the challenge to develop drugs that target an ever-growing list of proteins associated with diseases. However, an increase in the number of drugs approved every year is nowadays still not observed. To overcome this gap, innovative approaches should be applied in drug discovery for target validation, and at the same time organic synthetic chemistry has to find new fruitful strategies to obtain biologically active small molecules not only as therapeutic agents, but also as diagnostic tools to identify possible cellular targets. In this context, in view of the multifactorial mechanistic nature of cancer, new chimeric molecules, which can be either antitumor lead candidates, or valuable chemical tools to study molecular pathways in cancer cells, were developed using a multitarget-directed drug design strategy. According to this approach, the desired hybrid compounds were obtained by combining in a single chemical entity SAHA analogues, targeting histone deacetylases (HDACs), with substituted stilbene or terphenyl derivatives able to block cell cycle, to induce apoptosis and cell differentiation and with Sorafenib derivative, a multikinase inhibitor. The new chimeric derivatives were characterized with respect to their cytotoxic activity and their effects on cell cycle progression on leukemia Bcr-Abl-expressing K562 cell lines, as well as their HDACs inhibition. Preliminary results confirmed that one of the hybrid compounds has the desired chimeric profile. A distinct project was developed in the laboratory of Dr Spring, regarding the synthesis of a diversity-oriented synthesis (DOS) library of macrocyclic peptidomimetics. From a biological point of view, this class of molecules is extremely interesting but underrepresented in drug discovery due to the poor synthetic accessibility. Therefore it represents a valid challenge for DOS to take on. A build/couple/pair (B/C/P) approach provided, in an efficient manner and in few steps, the structural diversity and complexity required for such compounds.