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LA RESPONSABILITA' DA REATO DELL'ENTE PER GLI ILLECITI AMBIENTALI IN ITALIA E NEL REGNO UNITO
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Statistical characterization, analysis and modeling of speed performance in digital standard cell designs subject to process variations
No full textVerso una possibile integrazione dell'Icnotassonomia nella Sistematica dei vertebrati paleozoici
No full textIdentification of the mechanism for physiological hepatocyte polyploidization
No full textPolyploidy is the condition in which a cell possesses more than
two sets of homologous chromosomes. Although polyploidy is
not common in mammalians, some specific tissues including
heart, muscle cells, megakaryocytes, trophoblast giant cells and
parenchyma liver cells are physiologically polyploid. In liver
an extensive polyploidization occurs during the weaning period
between the 15th and 40th day after birth, leading to the
formation of tetraploid and octapoloid cells with one or two
nuclei. Polyploid hepatocytes retain an highly proliferative
potentiality; they can undergo multipolar mitosis due to extra
centrosomes generating 3 or 4 aneuploid daughter cells.
Hepatic aneuploidy was proposed to be a substrate for selection
of more resistant clones during liver injury. In fact it has been
demonstrated that specific aneuploid injury resistant nodules
emerged after chronic liver damage. However, how
polyploidization is triggered, established and regulated remains
an open question. Several data suggest that microenvironmental
elements (mainly soluble factors), rather than
cell autonomous mechanisms, play a direct role in the
appearance of polyploidy. For example, insulin and T3 hormone were identified as positive regulators and TGFα as a
negative regulator of the binucleation. We screened the effects
of a set of soluble factors involved in liver development and/or
mass liver control on a murine hepatocyte cell line. Within the
screening, we identified the cytokine TGFβ as a strong inducer
of hepatocyte binucleation. Time lapse video microscopy
highlighted that binucleated cells originated from a mechanism
of cytokinesis failure without affecting the kinetics of the
mitosis; this suggests that binucleation is a physiological
alternative program of hepatocyte division. Very interestingly,
in vivo experiments performed with the oral administration of a
TGFβ receptor chemical inhibitor, during days 18-32 post-birth
in mice, produced a significant decrease of binucleated
hepatocytes, confirming the crucial role played by this cytokine
in the polyploidization of the liver cells. In-vivo data showed
that the hepatocytes cellular model recapitulated the
physiology of the whole organism. Analysis of TGFβ
downstream elements, known to be involved in cytoskeleton
rearrangement, showed that Src kinase activity has a role in the
polyploidization process of hepatocytes, most probably through
the control of the GTPase protein RhoA, an actin cytoskeleton
regulator, crucial for the cytokinesis. In TGFβ treated cells, in fact, together with the activation of Src, we observed a
delocalization from the mid-body structure of the active form
of RhoA. TGFβ is well known to trigger Epithelial to
Mesenchymal Transition (EMT) in hepatocytes. The TGFβ-
induced binucleated cells, in fact, showed a fibroblastoid
morphology with upregulation of mesenchymal markers and
downregulation of epithelial ones. TGFβ withdrawal was also
performed and it produced an increase in ploidy levels with the
appearance of an octaploid population and giant nuclei.
Together with a ploidy increase, TGFβ withdrawal triggered
the Mesenchymal to Epithelial Transition (MET) characterized
by upregulation of ephitelial markers and downregulation of
mesenchymal markers and generating a full epithelial
polyploid population. In conclusion, TGFβ seems to be one of
the major stimuli for hepatocyte binucleation; it acts through
Src kinases and involves the activity of RhoA during
cytokinesis. Moreover, intriguing is the relationship between
EMT/MET and polyploidization that might reveal a new
biological process in which these transdifferentiation
mechanisms are involved and thus, requires further study
Statistical mechanics for biological applications: Focusing on the immune system
No full textThe emergence in the last decades of a huge amount of data in many fields of biology triggered also an increase of the interest by quantitative disciplines for life sciences. Mathematics, physics and informatics have been providing quantitative models and advanced statistical tools in order to help the understanding of many biological problems. Statistical mechanics is a field that particularly contributed to quantitative biology because of its intrinsic predisposition in dealing with systems of many strongly interacting agents, noise, information processing and statistical inference.
In this Thesis a collection of works at the interphase between statistical mechanics and biology is presented. In particular they are related to biological problems that can be mainly reconducted to the biology of the immune system.
Beyond the unification key given by statistical mechanics of discrete systems and quantitative modeling and analysis of the immune system, the works presented here are quite diversified. The origin of this heterogeneity resides in the intent of using and learning many different techniques during the lapse of time needed for the preparation of the work reviewed in this Thesis. In fact the work presented in Chapter 3 mainly deals with statistical mechanics, networks theory and networks numerical simulations and analysis; Chapter 4 presents a mathematical physics oriented work; Chapter 5 and 6 deal with data analysis and in particular wth clinical data and amino acid sequences data sets, requiring the use of both analytical and numerical techniques.
The Thesis is conceptually organized in two main parts. The first part (Chapters 1 and 2) is dedicated to the review of known results both in statistical mechanics and biology, while in the second part (Chapters 3, 4 and 6) the original works are presented together with briefs insights into the research fields in which they can be embedded.
In particular, in Chapter 1 some of the most relevant models and techniques in statistical mechanics of mean field spin systems are reviewed, starting with the Ising model and then passing to the Sherrington-Kirkpatrik model for spin glasses and to the Hopfield model for attractors neural networks. The replica method is presented together with the stochastic stability method as a mathematically rigorous alternative to replicas.
Chapter 2 is dedicated to a very schematic overview of the biology of the immune system.
In Chapter 3, Section 3.1 is dedicated to the presentation of a mathematical phenomenological model for the study of the idiotypic network while Section 3.2 serves as a review of the statistical mechanics based models proposed by Elena
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Agliari and Adriano Barra as toy models meant to underline the possible role of complex networks within the immune system.
In Chapter 4 the mathematical model of an analogue neural network on a diluted graph is studied. It is shown how the problem can be mapped in a bipartite diluted spin glass. The model is rigorously solved at the replica symmetric level with the use of the stochastic stability technique and fluctuations analysis is used to study the spin glass transition of the system. A topological analysis of the network is also performed and different topological regimes are proven to emerge though the tuning of the model parameters.
In Chapter 5 a model for the analysis of clinical records of testing sets of patients is presented. The model is based on a Markov chain over the space of clinical states. The machinery is applied to data concerning the insurgence of Tuberculosis and Non-Tuberculous Infections as side effects in patients treated with Tumor Necrosis Factor inhibitors. The analysis procedure is capable of capturing clinical details of the behaviors of different drugs.
Lastly, Chapter 6 is dedicated to a statistical inference analysis on deep sequencing data of an antibodies repertoire with the purpose of studying the problem of antibodies affinity maturation. A partial antibodies repertoire from a HIV-1 infected donor presenting broadly neutralizing serum is used to infer a probability distribution in the space of sequences that is compared with neutralization power measurements and with the deposited crystallographic structure of a deeply matured antibody. The work is still in progress, but preliminary results are encouraging and are presented here.FIRB grant RBFR08EKEV; Human Genetics Foundation, Torino
Exploring bonding interactions of biochemical relevance in silicon, platinum(II) and iron(III) positively charged species
No full textElements playing a biological role that are present in nature or in synthetic drugs, such as silicon, platinum(II) and iron(III) usually appear coordinated to ligands in more or less composite molecular architectures. This notion is particularly true when a metal ion is placed in the active center of an enzyme or otherwise integrated into simple biomolecules and proteins. Whereas multifaceted factors affect a charged (metal) centre in a biological environment, the gas-phase provides an interesting medium for elucidating intrinsic interactions between metal ions and biological targets. The idea underlying this doctoral thesis is to highlight how state of the art techniques combining mass spectrometry, IR spectroscopy and computational chemistry can be applied to the study of ionic complexes in an isolated state. In a first section the reactivity behavior of gaseous complexes from the (CH3)3Si+ addition to acetylene has been fully explored by FT-ICR mass spectrometry and ab initio calculations. In this way the C5H11Si+ potential energy surface has been elucidated and the computational results nicely account for the experimental evidence showing an isomerization process from a primarily formed complex (a β-silyl-substituted vinyl cation acquiring an asymmetric cyclic geometry) to CH2=C(CH3)-Si(CH3)2+ silyl cation. The computational methods tested in dealing with the C5H11Si+ ion problem have been further applied to more challenging systems. In a second and third section a comprehensive investigation of the structural features of the key intermediates which are formed from cisplatin by replacement of chloro ligands by water or methionine is described. Here the experimental approach has involved vibrational spectroscopy carried out with a recently designed and assembled apparatus. The NH/OH stretching region has been found highly structurally diagnostic in the aqua complexes where hydrogen bonding interactions are crucial in determining relative conformer stability. The infrared characterization of the monofunctional adducts of platinum(II) drugs with methionine has led to identify distinct modes of interaction with cisplatin and transplatin derived species. In fact, the preferred ligand atom (S or N) seems to be depending on the specific isomer (cis- or trans-) that is reacting with the metal. Cisplatin and transplatin derived species have been sampled both experimentally and computationally, taking into account relativistic effects in the heavy metal. In a fourth task the binding properties of azole ligands toward ferric heme have been examined. Starting from simple ligands such as pyridine, 1-methylimidazole and 1H-1,2,4-triazole, the focus was then directed to imidazole- and triazole-based antifungal drugs. These drugs are known to act as inhibitors of CYP51enzyme, through binding to the heme prosthetic group. Relative binding energies were determined experimentally by energy variable collision induced dissociation experiments performed on the selected ionic complexes and evaluated theoretically by Car-Parrinello molecular dynamics calculations. To this end, theoretical investigations were carried out during a training period spent at the “Parc Cientific de Barcelona”, under the supervision of Research Professor Carme Rovira. Imidazole-based drugs consistently display higher dissociation energies when compared to triazole-based drugs
La forma della città e la vitalità dello spazio pubblico urbano
No full textThe urban space can be considered lively when things happen there: a lot of people move around generating chances for interaction and for economic and cultural activities. Urban vitality consists thus in the very essence of the city in its ancestral meaning of an active community of individuals, which has been too often put aside by modern and contemporary urban reflections and design proposals. The current time of crisis of the collective realm, the virtualization of interpersonal relations and the attention to the global scale instead of the local one lead to ask what it will be of the urban everyday life, especially regarding its most basic declinations such as the proximity relations. The human activity in the cities – as Jan Gehl reminds us – is conditioned by a number of factors, many of which have to do with the environmental and behavioral sphere. A major set of conditioning factors, however, has to do with the fisical and relational configuration of the city. The relation between the fisical characters of the city and the expression of the urban life can be traced by analyzing the form of the city and its topological features with an appropriate metodology, as well as scientifically observing the way people act in the urban space. Finding out about how deep can a set of characters of the urban form influence vitality can result in an enormously useful tool for the development of new urban areas as well as for the requalification of existing dull neighbourhoods, a task many western cities are nowadays called to answer to
