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Truncated erythropoietin receptor as a selectable marker for gene therapy of haematopoietic stem cells.
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Synthesis and biological evaluation of new inhibitors of HIV-1 protease dimerization and αVβ3-integrin atagonists with pptidomimetic Structures.
No full textDespite the versatile and interesting function of peptides in biological systems, metabolic instability and poor bioavailability make them ineffective as orally administered drugs. Due to these limitations, peptidomimetic compounds are preferred as drug candidates.
This thesis deals with the design and the synthesis of peptidomimetics.
In the Chapter I, peptidomimetics were introduced in molecular tongs as dimerization inhibitors of wild-type and mutated HIV-1 Proteases.
HIV-1 protease (PR) is a homodimer of two identical 99-amino acid subunits in which the active site is generated by self-assembly of these subunits. Remarkably, the antiparallel ßsheet formed by interdigitation of N- and C-terminal strands of each protease monomer, which contributes over 75 % to the stabilizing force of the dimer, is found relatively free of mutations. By targeting this highly conserved dimerization interface, we demonstrated that HIV-1 protease dimer is disrupted with loss of activity by constrained molecular tongs based on naphthalene scaffold. We describe here the synthesis, the enzyme inhibitory activity against wild-type and mutated HIV-1 PR, of new molecular tongs containing amino acid mimetic fragments in one or two strands.
In the Chapter II, diketopiperazine scaffold was introduced in cyclic RGD peptidomimetics, as new integrin inhibitors.
Synthetic peptides and peptidomimetics, containing the arginine-glycine-aspartate (RGD) motif, have been widely used as inhibitors of integrin-ligand interactions to study cell growth, adhesion, migration and differentiation. In many cases, the RGD sequence is combined with a secondary structure inducing element to form cyclic peptidomimetics. In this project, a few cyclic peptidomimetics containing a bifunctional diketopiperazine (DKP) unit (cis and trans) and the RGD sequence, were prepared by solution phase peptide synthesis, and tested as selective ligands for the integrins αvβ3 and αvβ
Pharmacological modulation of human polymorphonuclear leukocyte functions: from basic studies to clinical investigations.
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Study of organic and inorganic size-segregated chemical composition of different types of tropospheric aerosol.
No full textTropospheric aerosol influences several important chemical and physical processes in the troposphere, due to its high variability in terms of origin, chemical composition, size-distribution and spatial distribution. In fact local and regional, biogenic and anthropogenic, primary and secondary sources as well as long-range transport affect aerosol properties over independent regions and layers.
For these reasons organic and inorganic chemical composition at the different size ranges must be well characterized in order to understand and properly described in models the physical and chemical processes occurring in the troposphere.
The present thesis provides a detailed description of factors controlling size-segregated inorganic and organic chemical properties of different types of tropospheric aerosol. Size segregated aerosol samples were collected during the experiments performed in 2006 within the European Project MAP (Marine Aerosol Production Project, http://macehead.nuigalway.ie/map/), and during three intensive campaigns performed in 2007 and 2008 within the Italian project MIUR-AEROCLOUDS (Study of the Direct and Indirect Aerosol Effects on Climate). A chemical characterization of both water soluble and water insoluble organic fractions and water insoluble inorganic ions was accomplished.
In the framework of the Project MAP, main primary and secondary marine aerosol chemical components were investigated under clean marine conditions with relation to seasonal oceanic biological activity. Typical marine aerosol features were observed. Non sea salt sulphate (nss-SO4=) and ammonium (NH4+) dominated the submicrometer inorganic fraction, nitrate (NO3-) and sea salt are mainly distributed in the supermicrometer fraction but sea salt largely controlled the chemical composition of the supermicrometer particles. Water soluble (WSOM) and water insoluble (WIOM) organic matter mostly distributed in submicrometer particles with a large contribution. Primary organic matter (OM) resulted mostly insoluble and mainly produced by bubble bursting processes at the sea surface, as shown by Bubble Bursting experiments performed during MAP and thus indicating the prevalent secondary origin of WSOM.
The overall results clearly evidenced that concentration of the main secondary components (nss-SO4=, NH4+, WSOM, MSA) are driven by seasonality of oceanic biological productivity.
Furthermore, a new secondary component, alkylammonium salts, has been detected in marine aerosol samples. Dimethyl- (DMA+) and diethyl- (DEA+) ammonium, resulted the most abundant organic species, second only to MSA, detected in fine particles. These two species accumulate in submicrometer marine aerosol via acid-base reaction between gaseous biogenic amines and acidic sulphates. DMA+ and DEA+ show in analogy to the other biogenic secondary components, a variation in concentration clearly driven by biological activity. This result point to a potential important new source of marine SOA and atmospheric nitrogen at the global scale with a seasonal variation connected to the oceanic biological productivity.
In the framework of the project AEROCLOUDS, night-time and daytime size segregated aerosol samples were collected concurrently at the urban site of Torre Sarca (Milan), at the urban background site of Ispra (VA), at the rural site of San Pietro Capofiume (Bologna), at the mountain site of Mt. Cimone (2165 m a.s.l.) and at the urban background site of Montelibretti (Rome), during three typical patterns of the aerosol climatology in Italy:
• Aerosol accumulation in summer anticyclonic conditions (14 to18 July 2007);
• Aerosol accumulation in winter anticyclonic conditions (6 to 10 February 2008);
• Saharan dust long-range transport in spring (23 to 27 May 2007).
At the stations located within the Po basin (Milan, Ispra and San Pietro Capofiume), the main chemical aerosol components exhibited typical seasonal features observed in other highly populated and industrialized European areas. Organic compounds and nitrate maximises in winter. Sulphate exhibits higher background levels and a higher relative contribution in summer as its formation is related to photochemical activity. Sulphate and nitrate mainly occur as ammonium salts in the fine fraction as suggested by ionic balance. The winter maximum of organics, nitrate and ammonium mass concentration results in an increase in particulate matter levels due to different mechanisms which during stable atmospheric conditions occur favouring gas to
particles conversion of semi-volatile components such as ammonium nitrate and organics. The enhanced nucleation and condensation together with higher emission of fine particles accounts for a net increase of fine aerosol mass with respect to coarse mass as suggested by higher PM1/PM10 mass ratio in winter. Furthermore different diurnal cycle of boundary layer between wintertime and summertime induces differences in diurnal variation of aerosol concentration and chemical composition because in winter, when daytime mixing is very limited in height and time, the diurnal variability in aerosol mass concentration and chemical composition is less pronounced than in summer.
The night-time-daytime WSOC/TC ratio values during wintertime and summertime highlighted that higher photochemical activity enhances atmospheric oxidation processes converting biogenic and anthropogenic emissions of organic compounds into a more water soluble form and, therefore, secondary organic aerosol (SOA) formation.
At the mountain site of Mt. Cimone, differently from the Po valley stations, the daytime aerosol concentrations showed a clear seasonal pattern with the highest concentration in summer and the lowest in winter. This trend likely reflected the higher efficiency of vertical air masses transport during warmer months suggesting that daytime valley breezes and convective processes might transport polluted air masses from the regional boundary layer to the mountain site. Conversely, wintertime and night-time observations were less affected by influences from the PBL and are representative of the free tropospheric European baseline as suggested by fine aerosol chemical composition rich in sulphate and water-soluble organic compounds and poor in fine particulate nitrate and water insoluble carbonaceous compounds.
The impact of dust transport resulted in the increase in bulk aerosol mass concentration during dust transport, in the increased concentration of water soluble calcium in the coarse fraction and in the decrease in PM1/PM10 mass ratio values at all stations with respect to regional background conditions. These changes are all attributable to enrichment into coarse particles of crustal material of Saharan origin.
Furthermore we observed two chemical features indicating aerosol ageing during transport from North-African regions: the increase of WSOC contribution to TC and the
shift of nitrate size distribution in the coarse range at Mt. Cimone showing that mineral dust occurred at synoptic scale.
The impact of Saharan dust transport strongly affected total mass and chemistry of background aerosol at Mt. Cimone, while in urban and polluted sites at lower elevation, the impact on aerosol chemistry was much less pronounced even if specific markers such as calcium revealed that transport occurred
Eco-ethological characterization of the alien slider Trachemy scripta and evaluation of the effects of its introduction on the conservation of Emys orbicularis.
No full textIn the field of computational linguistics, the representation of natural languages (NL) in formal grammar terms is a well-known issue and a wicked problem indeed. In fact, some formal grammars lack of lexical and semantic information representation, reducing the linguistic structure to syntax.
On the other side, approaches like dependency grammars lose expressive power, under a computational point of view. Adpositional grammars (adgrams) are a novel grammar formalism that overcomes these limitations.
Adgrams are based on Pennacchietti’s intuition, who put together Brøndal’s logic description of prepositions, Tesnerian notion of valence, Langacker’s cognitive dichotomy trajector/landmark and Silvio Ceccato’s pioneer work in the field on machine translation (MT). The result is a quasiformal description of adpositions, being the junctors of language structure.
This description is called adpositional space. Each adpositional space is made of four adpositional types: Plus (#), Minus (), Slash (!), Times ()). The resulting structure is cognitively sound and formally inspiring, as adpositional trees (adtrees) can be built as special Porphyrian trees, going beyond the Tesnerian somehow fuzzy concept of dependency.
This dissertation puts Pennacchietti’s work a step forward. In fact, here adgrams consider the ultimate unit of NLs being the morpheme, not the word, and therefore they offer a coherent theory of both morphology and syntax. Hence, the collocation phenomena are considered like zero morphemes.
Moreover, a sharp distinction in the dictionary between the adpositional space, essentially made of closed morphemes, and the lexicon, made of open morphemes. Moving again from Tesnerian structural syntax, open morphemes always have a fundamental grammar character: stative (O), adjunctive (A, as stative modifiers), and verbal (I), circumstantial (E, as verbal modifiers). The Tesnierian approach is validated through Whorf’s research results comparing grammars of typologically distant NLs.
The second part shows that adgrams are computable, as they can be implemented with a strong, robust formalism. A concrete instance of the formal model of adgrams is given through the quasi-natural language Esperanto (QNL, Lyons), showing the linguistic viability of the model. The formal model should be used appropriately in an ad hoc epistemological scenario, called ‘the translation game’, designed as a Gedankenexperiment `a la Turing. A toy example is also given. In the third part the implementation is explained with all its details: the implementation of Esperanto is made in exactly 179 logic formulas, 56 of which are predicates. The formal model is promising to be generalised for any NLs, and how to do this was explained in various points of the third part. Finally, this dissertation shows that adgrams are a powerful NL grammar formalism which is at the same time cross-linguistic, cognitively grounded and formally robust and computationally sound.
In the field of computational linguistics, the representation of natural languages (NL) in formal grammar terms is a well-known issue and a wicked problem indeed. In fact, some formal grammars lack of lexical and semantic information representation, reducing the linguistic structure to syntax.
On the other side, approaches like dependency grammars lose expressive power, under a computational point of view. Adpositional grammars (adgrams) are a novel grammar formalism that overcomes these limitations.
Adgrams are based on Pennacchietti’s intuition, who put together Brøndal’s logic description of prepositions, Tesnerian notion of valence, Langacker’s cognitive dichotomy trajector/landmark and Silvio Ceccato’s pioneer work in the field on machine translation (MT). The result is a quasiformal description of adpositions, being the junctors of language structure.
This description is called adpositional space. Each adpositional space is made of four adpositional types: Plus (#), Minus (), Slash (!), Times ()). The resulting structure is cognitively sound and formally inspiring, as adpositional trees (adtrees) can be built as special Porphyrian trees, going beyond the Tesnerian somehow fuzzy concept of dependency.
This dissertation puts Pennacchietti’s work a step forward. In fact, here adgrams consider the ultimate unit of NLs being the morpheme, not the word, and therefore they offer a coherent theory of both morphology and syntax. Hence, the collocation phenomena are considered like zero morphemes.
Moreover, a sharp distinction in the dictionary between the adpositional space, essentially made of closed morphemes, and the lexicon, made of open morphemes. Moving again from Tesnerian structural syntax, open morphemes always have a fundamental grammar character: stative (O), adjunctive (A, as stative modifiers), and verbal (I), circumstantial (E, as verbal modifiers). The Tesnierian approach is validated through Whorf’s research results comparing grammars of typologically distant NLs.
The second part shows that adgrams are computable, as they can be implemented with a strong, robust formalism. A concrete instance of the formal model of adgrams is given through the quasi-natural language Esperanto (QNL, Lyons), showing the linguistic viability of the model. The formal model should be used appropriately in an ad hoc epistemological scenario, called ‘the translation game’, designed as a Gedankenexperiment `a la Turing. A toy example is also given. In the third part the implementation is explained with all its details: the implementation of Esperanto is made in exactly 179 logic formulas, 56 of which are predicates. The formal model is promising to be generalised for any NLs, and how to do this was explained in various points of the third part. Finally, this dissertation shows that adgrams are a powerful NL grammar formalism which is at the same time cross-linguistic, cognitively grounded and formally robust and computationally sound
Molecular characterization of CDKL5 in the nervous system and in the pathogenesis of rett syndrome.
No full textRett syndrome (RS) is an X-linked neurodevelopmental disorder that represents the second cause of mental retardation in females. Symptoms manifest after a period of apparently normal development and are characterized by stereotypic hand movements, mental retardation, epileptic crisis, hyperventilation, constipation and cardiovascular abnormalities. The vast majority of patients affected by the classical form of RS carries mutations in the methyl-CpG binding protein 2 (MeCP2), a ubiquitous protein that, binding to methylated promoters, represses the transcription of downstream genes. Moreover, according to the fact that RS is exclusively a neurological disease, MeCP2 has been recently shown to dynamically modulate the transcription of specific neuronal genes, such as Bdnf. Importantly, the phosphorylation of MeCP2 has been demonstrated to be required for Bdnf transcription upon neuronal activity.
Besides the classical form of RS, also a number of variants have been reported: some of them cause a milder clinical picture than the classical form, while others display a more severe phenotype. Among the latter, the Hanefeld variant characterized by the absence of an initial asyntomatic period and by the early onset of pharmacologically untreatable seizures. Several patients affected by this variant have been found to carry mutations in the cyclin dependent kinase like 5 (CDKL5), a serine/threonine kinase made up of an N-terminal catalytic domain and a long and uncharacterized C-terminal tail. Previous publications demonstrated that CDKL5 and MeCP2 interact physically and that the kinase is able to autophosphorylate and to mediate the phosphorylation of recombinant MeCP2 in vitro. The aim of this work was to elucidate the impact of RS causing mutations in CDKL5 on its physiological functions as well as its expression pattern in adult and developing brain. The kinase activity, subcellular localization, and protein stability of different RS causing missense or truncating mutations have been analyzed in comparison to the wild type protein. The Δ781 mutant, lacking the last 250 aa of the protein, revealed to be catalytically hypermorphic: in fact, both the auto- and the heterophosphorylation activity of this mutant were increased if compared to the wild type protein. Moreover, when overexpressed in cells, it accumulated exclusively in the nucleus, loosing the capability to shuttle between the two main cellular compartments, as the wt protein does. Also its half-life was altered, showing a reduced degradation rate when compared to the wt kinase. In parallel, the analysis of other truncated mutants showed an altered subcellular localization and proteasomal degradation when the very C-terminal tail of the protein was missing. These results clearly suggest a pivotal role played by the last 200 aa of CDKL5 in the modulation of its catalytic activity, the regulation of its nucleo-cytoplasmic shuttling and its degradation. The concomitant analysis of two disease causing missense mutations of CDKL5, C152F and R175S, revealed that point mutations affecting the catalytic domain of the protein strongly impair its functions. In fact, conversely to the truncated mutants, the R175S and the C152F derivatives showed to be hypomorphic or catalytically inactive, respectively. According to the hypothesis that the catalytic activity of the protein is requested for CDKL5 to enter the nucleus, the hypomorphic and the kinase dead artificial derivative, K42R, were retained in the cytosolic compartment. All together, these results indicate that altered subcellular localization and expression levels of CDKL5 might be the origin of a pathological state. In parallel, also the expression pattern of endogenous murine protein in a physiological context was analysed. The western blot experiments performed on adult mouse tissues revealed that CDKL5 expression is heterogeneous: this kinase was, in fact, virtually absent in some brain districts (hypothalamus and cerebellum), while it was well expressed in others (cortex, hippocampus, striatum and thalamus). Also its subcellular localization differed depending on the brain region: in the majority of the analysed areas, its cytosolic and nuclear fraction were almost equally represented, while in cerebellum and striatum the amount of cytosolic protein widely exceeded the nuclear one. These data suggest that in mammalian brain CDKL5 expression and localization are tightly regulated both at a regional and at a cellular level. The analysis of the same features in new born mice showed the importance of CDKL5 in the delicate process of postnatal development. In fact, the expression level of this protein was strongly upregulated in the first days of postnatal life, decreasing, then, to lower levels in the adulthood. Concomitantly, the nuclear fraction of the kinase gradually increased during postnatal development, being almost absent in the first days of life and reaching the 40% of total protein in adult mouse brain. Finally, the involvement of CDKL5 in the process of neuronal maturation and differentiation is also suggested by the experiments performed in Neuro-2a cells with the shRNA tool: the long term silencing of the kinase, in fact, prevented neurite extension upon induction of differentiation.
Taken together, the results showed in this work indicate that the RS pathological state may be correlated to an altered capability of the mutated protein (i) to phosphorylate its substrates (itself or other targets), (ii) to be properly localized within the cell, and (iii) to be readily degraded by the proteasome. Moreover, the study performed in the developing mouse brain and in Neuro-2a cells has suggested a role of the kinase in postnatal development and neuronal differentiation. Further work will be aimed to investigate more in detail this interesting issue
Valutazione dell'esposizione individuale al particolato urbano ed agli inquinanti gassosi ad esso correlati nell'ambito del progetto PM-CARE.
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The redshift dependence of the MBH–Mhost relation in quasars.
No full textThis Thesis is focused on the study of the evolution of the MBH–Lhost, Mhost relations
as a function of redshift. The aim is to probe whether (and how) the black hole – host galaxy relations evolve during Cosmic ages. This would contribute in constraining the possible formation histories of galaxies and in unveiling the mechanisms regulating the co-existence of black holes and galaxies.
The present study addresses the joint evolution of black holes and galaxies from an observational point of view. Our sample consists of 96 quasars with 0 < z < 3, half of which are radio loud (chapter 2). The stellar luminosities of the host galaxies are taken from imaging studies available in the literature, and from new observations led by our group (chapter 3). The stellar mass is derived from the host galaxy luminosity, under certain assumptions on
the star formation history of the galaxy (chapter 4). Spectroscopic determinations of the black hole masses are derived from the analysis of new data taken on purpose (chapters 3 and 5). The whole dataset is available in the appendix sections A and B. From the study of the MBH/Mhost ratio at low-z, where evolutionary effects are negligible, we infer some constraints
on the geometry of the broad line region. When moving to high redshift (z = 2−3),
we find that the MBH–Lhost relation is practically unchanged. On the other hand, because of the evolution of the stellar mass-to-light ratio, the MBH–Mhost relation shows a clear evolution, in the sense that, for a given host galaxy mass, black holes at high redshift are ∼ 8 times more massive than their low-z counter-parts. This trend cannot be explained in terms of selection effects, and is confirmed after relaxing some operative assumptions. Our results are compared to those of similar works available in the literature. Sketches of possible
interpretative scenarios are also discussed (chapter 6). Conclusions and future perspectives are presented in chapter 7.
The present work principally deals with the analyses and studies published in Decarli et
al. (2008a, on the broad line region geometry), Kotilainen et al. (2009, on the luminosity of quasar host galaxies at z > 2), Decarli et al. (2009b, on the spectroscopic dataset) and Decarli et al. (2009c, on the evolution of the BH–host galaxy relations). A complete list of my publications during the PhD is provided in appendix C
Adpositional grammars: a multilingual grammar formalism for NLP.
No full textIn the field of computational linguistics, the representation of natural languages (NL) in formal grammar terms is a well-known issue and a wicked problem indeed. In fact, some formal grammars lack of lexical and semantic information representation, reducing the linguistic structure to syntax.
On the other side, approaches like dependency grammars lose expressive power, under a computational point of view. Adpositional grammars (adgrams) are a novel grammar formalism that overcomes these limitations.
Adgrams are based on Pennacchietti’s intuition, who put together Brøndal’s logic description of prepositions, Tesnerian notion of valence, Langacker’s cognitive dichotomy trajector/landmark and Silvio Ceccato’s pioneer work in the field on machine translation (MT). The result is a quasiformal description of adpositions, being the junctors of language structure.
This description is called adpositional space. Each adpositional space is made of four adpositional types: Plus (#), Minus ($), Slash (!), Times ()). The resulting structure is cognitively sound and formally inspiring, as adpositional trees (adtrees) can be built as special Porphyrian trees, going beyond the Tesnerian somehow fuzzy concept of dependency.
This dissertation puts Pennacchietti’s work a step forward. In fact, here adgrams consider the ultimate unit of NLs being the morpheme, not the word, and therefore they offer a coherent theory of both morphology and syntax. Hence, the collocation phenomena are considered like zero morphemes.
Moreover, a sharp distinction in the dictionary between the adpositional space, essentially made of closed morphemes, and the lexicon, made of open morphemes. Moving again from Tesnerian structural syntax, open morphemes always have a fundamental grammar character: stative (O), adjunctive (A, as stative modifiers), and verbal (I), circumstantial (E, as verbal modifiers). The Tesnierian approach is validated through Whorf’s research results comparing grammars of typologically distant NLs.
The second part shows that adgrams are computable, as they can be implemented with a strong, robust formalism. A concrete instance of the formal model of adgrams is given through the quasi-natural language Esperanto (QNL, Lyons), showing the linguistic viability of the model. The formal model should be used appropriately in an ad hoc epistemological scenario, called ‘the translation game’, designed as a Gedankenexperiment `a la Turing. A toy example is also given. In the third part the implementation is explained with all its details: the implementation of Esperanto is made in exactly 179 logic formulas, 56 of which are predicates. The formal model is promising to be generalised for any NLs, and how to do this was explained in various points of the third part. Finally, this dissertation shows that adgrams are a powerful NL grammar formalism which is at the same time cross-linguistic, cognitively grounded and formally robust and computationally sound