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A quantitative model for the asset liability management of a Pension Fund
Get PDFThe key objective of pension plans is the delivery of retirement benefits, typically payable for life or a set period of time, to the specified group of recipients. The management of such funds entails therefore a constant monitoring of the risks exposure and a regular rebalancing of assets.
This thesis is directly related to these topics and proposes a quantitative method (mainly based on stochastic optimal control theory) to determine the optimal investment policy of a pension fund’s wealth, under financial and actuarial risks.
The thesis unfolds as follows: Chapter 1 includes a basic introduction to pension systems. The topics addressed here are: how to classify pension systems, the main characteristics of each kind of system, examples of major systems and the important reforms that have been implemented in Italy; the chapter ends with a description of Italian professional order pension funds. Chapter
2 describes asset liability management techniques in pension schemes; it contains a review on major literature on asset liability management and a discussion on interested parties in this topic and on policies and instruments which can be adopted. Chapter 3 contains an original model to determine the optimal financial investment policy in a pension fund, considering both financialand actuarial risk. Moreover, the model takes care of the pension plan’s sustainability, i.e. of the balance between the active and retired members.
Chapter 4 is a numerical application of the model described in the previous chapter to a real Italian pension fund. Finally, in Chapter 5 conclusions are drawn related to the question asked
A computational approach for identification and development of novel inhibitors targeting viral polymerases
Get PDFPositive strand RNA viruses, which include hepatitis C virus (HCV), human immunodeficiency virus (HIV,
and Bovine Viral Diarrhea Virus (BVDV), are known to create havoc for humans and animal health alike.
Although vaccines have helped to control several of the most important viral pathogens, there is currently little
prospect of an effective vaccine for either HCV or HIV. These pathogens infect ~170 million and ~40 million
people worldwide, respectively, hastening the need for effective antiviral drugs. Likewise BVDV infects
domesticated livestock causing significant economic losses worldwide. The development of new, effective
antiviral compounds for combating these debilitating human (HIV and HCV) and animal pathogen (BVDV) is
therefore of paramount importance, and is the focus of this thesis.
Herein, polymerases of three positive strand RNA viruses, viz HCV, BVDV and HIV have been targeted with the
goal of improving the efficacy of antivirals against wide range of resistant mutations. Lack of effective therapies
for these viral infections as most of the established treatments are not always effective or well tolerated,
highlights an urgent need for further refinement and development of antiviral drugs. It is not only the specific
need that has inspired this work but also the idea to test and develop protocols that might enable a more
rational structurebased
drug design to be performed by keeping a tradeoff among rapidity, accuracy, and
efficacy.
Traditional methods for general drug discovery typically include evaluating random compound libraries for
activity in relevant cellfree
or cellbased
assays. Success in antiviral development has emerged from the
discovery of more focused libraries that provide clues about structureactivity
relationships. Combining these
with more recent approaches including structural biology and computational modeling can work efficiently to
hasten discovery of active molecules. The ability to design drugs interfering with the progression of infection
of virus comes with i)the
knowledge of pathological, cellular and molecular mechanism involved in the
disease; and ii)the
identification of macromolecule (i.e possible drug target) involved in pathological
pathways, their 3D structures and their functions. The biological activity of drug molecules is dependent on
the threedimensional
arrangement of its functional groups, which specifically bind to their target.
Consequently, the structural information of the target protein is essential in drug development.
Proteins are dynamic molecules and often undergo conformational change upon ligand binding. The flexible
loop regions and in general the flexibility of the structure have a critical functional role in enzymes, but those
features and their connection with the functionality of protein are hard to retrieve from xray,
NMR techniques
and cryoEM
techniques.
Being aware of the importance of the relationship structurefunction
and structureactivity
at large, i.e.,
including dynamics and interactions with solvent, in our work we are trying to address some of the relevant
problems of drug development; basic key determinants in proteinligand
stability, mechanism of inhibition,
why and how, flexibility and collective motion of the protein is essential part in improvement of rational drug
design, how mutation renders the protein resistant again potent drugs; the effect of resistance mutation on the
flexibility and stability of protein, what is the mechanism of drug resistance, change in energetics
consequences, affecting the conformation in wild and mutant systems. Various biophysical techniques of the
computational arsenal we have applied have provided huge wealth of information related to protein dynamics
and proteinligand
recognition. These methods have grown in their effectiveness not only by offering a deeper
understanding of the basic science, the biological events and molecular interactions that define a target for
therapeutic intervention, but also because of advances in algorithms, representations, and mathematical
procedures for studying such processes.
This work represents the application of several computational techniques, such as docking, molecular
dynamics, algorithms to calculate free energy of binding of ligands into the binding pocket (ex MMPBSA)
and
algorithms to study rare events (for ex. binding and unbinding of ligand from the binding site, Metadynamics)
to explore, at microscopic level, the key pattern of interaction between protein and ligand, to understand the
effect of mutations, to get an insight of the full docking and undocking path and to calculate binding
energetics.
Phenotypic characterization and differentiation potential of cells from human placenta: new approaches of stem cell theraphy for cystic fibrosis
Get PDFCystic fibrosis (CF) is the most frequent severe autosomal recessive disorder in the European population. The gene is located on the long arm of chromosome 7 and encodes for CFTR protein (Cystic Fibrosis Transmembrane Conductance Regulator). Despite the disease involves different organs, the most clinically relevant symptoms are found in the lung. Recently, given the monogenic nature of CF, different gene therapy strategies have been developed, but the results show that the correction of the defect is only temporary. Therefore, a novel approach based on stem cell-based therapy for reconstitution of the airway epithelium and CFTR expression should be explored.
CF is a potential model disease for stem cell therapy because of the persistent lung inflammation that leads to damage and remodeling, and can promote engraftment of stem cells. If stem cells, transferred through autologous or heterologous transplant, would harbour in stem niches of respiratory epithelium, then the restoration of genetic and cellular damage will be definitive.
In the last years, several cell populations derived from adult bone marrow, amniotic fluid or umbilical cord blood, have been shown to differentiate in different epithelia, including respiratory. Even if the in vivo efficiency of bone marrow stem cells to differentiate in airway epithelium is very low, recent studies demonstrate that a small percentage of corrected cells is needed to revert the defect. Bone marrow mesenchymal stem cells are not without drawbacks, e.g. they are limited in numbers and lack well-defined markers required for their purification. One approach to overcome these limitations is to consider alternative sources of stem cells capable of repopulating damaged respiratory epithelium.
In the present study, we evaluated the possibility of obtaining stem cells from an ethically acceptable source as human placenta.
As a potential source of cells for application in CF therapy, the placenta has the advantage of being a natural by-product of birth which is often simply discarded, while harvest of term amniotic membrane does not pose any risk to the mother or newborn.
We demonstrated that amniotic membrane is a fetal tissue rich in cells with stem cell characteristics and with the capacity to remain “plastic” in their differentiation options. Furthermore, amniotic cells display features as low immunogenicity and non tumorigenicity.
For the first time, our results provided evidence that human amniotic epithelial cells (hAECs) and amniotic mesenchimal stromal cells (hAMSCs) can be induced in vitro to express markers of airway epithelial phenotype, like CFTR and ZO-1, particularly when co-cultivated with CF human epithelial bronchial cells, and so have the potential to differentiate into airway epithelial cells.
Overall, our data showed that these cells may contribute to partial correction of the CF phenotype and are very likely an ideal candidate for cell-based therapy for CF.
Whether the beneficial effects of placenta-derived cells are due to differentiation of the transplanted cells themselves or to paracrine actions on the surrounding host tissue in order to reduce inflammation and promote regeneration remains to be fully elucidated. In any case, the promising data obtained to date constitute compelling evidence regarding the potential utility of these cells for clinical application.
Future studies testing these cells in in vivo model, will help in finding a strategy of cell therapy for the cure of respiratory disease of CF, directly transferable to CF patients
Preparation, development and evaluation of novel drug delivery systems for colon targeting
Get PDFIl direzionamento di farmaci al colon sta assumendo un ruolo sempre più importante non solo per il targeting di farmaci usati nel trattamento di patologie del colon ma anche come sito per l’assorbimento e raggiungimento sistemico di proteine. Lo scopo di questo lavoro è stato quello di preparare diversi sistemi per il direzionamento al colon di due farmaci modello usati nel trattamento di patologie del colon: l’acido 5-amminosalicilico (5-ASA) e il metronidazolo (MTZ). Per la preparazione di questi sistemi sono stati scelti sistemi pH-dipendent ed enzima-dipendenti. Sistemi pH-dipendenti sono stati preparati con il 5-ASA. N-Succinyl-chitosano (SucCH) è stato usato come carrier grazie alle sue favorevoli proprietà per il direzionamento al colon. Sono stati preparati vari sistemi matriciali con il 5-ASA, chitosano e N-Succinyl-chitosano con e senza ciclodestrina, con lo scopo di valutare l’influenza della presenza della ciclodestrina nelle varie formulazioni. Infine sono state preparate microparticelle di 5-ASA e SucCH. Tutti i sistemi sono stati caratterizzati e sono stati effettuati studi di rigonfiamento e di rilascio, studi di mucoadesione e studi in vivo usando il modello di colite indotta da TNBS in ratti. Sistemi enzima-dipendenti sono stati preparati con il metronidazolo attraverso la sintesi di profarmaci del MTZ, legando covalentemente il farmaco alla α-, β- e γ-ciclodestrina e al chitosano. Tutti i profarmaci sono stati caratterizzati e sono stati effettuati studi di stabilità in vitro e studi di rilascio del farmaco ex vivo con il contenuto del cieco e del colon di ratti.
----------------------------------------------------------------------------------------------------------------------------Colon specific drug delivery has gained increased importance not only for drug delivery in the treatment of local colonic diseases but also as potential site for the systemic delivery of therapeutic peptides and proteins. The aim of this work was to develop different colon specific delivery systems by using two model drugs for the treatment of colon diseases: 5-aminosalicylic acid (5-ASA) and metronidazole (MTZ). Two different types of colon drug delivery systems were chosen: enzyme-dependent system and pH-dependent system. Different 5-ASA pH-dependent systems were developed for the treatment of IBD. N-Succinyl-chitosan was chosen as carrier system because it presents favorable properties for the delivery of drugs to the colon. 5-ASA loaded N-Succinyl-chitosan and chitosan matrices were prepared. β-cyclodextrin (CD) were loaded into the polymers and the influence of CD on the system characteristics was studied. 5-ASA loaded N-Succinyl-chitosan microparticles were also prepared. These systems were chemically and analytically characterized; in vitro swelling and release studies were performed, finally mucodhesion and in vivo studies using TNBS colitis rat model were carried out. Macromolecular prodrugs of MTZ and α-, β- and γ-cyclodextrin or chitosan (CHT) were prepared by linking the drug with a covalent bond to the macromolecule (CD or CHT). All the prodrugs were chemically and analytically characterized. In vitro stability and ex vivo release studies were performed to investigate their usefulness as colon delivery systems
Bio-ecologia e stato della risorsa Corallium rubrum (L. 1758) in Sardegna: fondamenti per una razionalizzazione della gestione
Get PDFLa nobile famiglia catalana dei Sanjust in Sardegna: ricostruzione del patrimonio archivistico e bibliografico
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Il disegno dei baluardi cinquecenteschi nell'opera dei fratelli Palearo Fratino: la piazzaforte di Alghero
Get PDFLa ricerca affronta il tema del disegno dei baluardi nell’opera dei fratelli Palearo Fratino, ingegneri
militari al servizio della Spagna nella seconda metà del XVI secolo e si struttura attraverso tre
principali fasi: la prima analizza il disegno del fronte bastionato nel corso del Cinquecento, la
seconda esamina l’attività progettuale di Jacopo e Giorgio Palearo nel Mediterraneo ed in
particolare in Sardegna, mentre la terza si propone attraverso l’utilizzo dei risultati provenienti dalle
prime due fasi di ricerca e con il supporto dei dati offerti dalle ricerche di archeologia
postmedievale, di elaborare alcuni modelli digitali di opere progettate e non realizzate o non più
esistenti della piazzaforte di Alghero. Il metodo di ricerca adottato trova nell’analisi grafica lo
strumento di indagine conoscitiva, capace di fornire informazioni e rilevanti risultati a supporto
dell’indagine storico-archeologica. L’analisi della trattatistica militare è rivolta in particolare al
testo “Della fortificatione delle città” del Maggi e Castriotto, citato da Jacopo Palearo come testo di
riferimento nella progettazione dei baluardi di Cagliari. Analizzati i progetti, eseguito il rilievo di
alcuni tratti rappresentativi di opere realizzate, si è individuato un repertorio che ha evidenziato
l’impiego (attraverso l’uso di soluzioni costruttive e modelli ricorrenti adattati in relazione alle
preesistenze ed al sito) del trattato del Maggi e Castriotto a conferma di quanto dichiarato da El
fratin. I dati provenienti dall’analisi della trattatistica e delle opere hanno infine costituito la base di
riferimento per l’elaborazione dei modelli digitali relativi ai progetti redatti nel periodo 1552-1578
per la realizzazione delle fortificazioni di Alghero e consentito di approfondire la conoscenza del
disegno degli ingegneri militari e dell’attività progettuale dei fratelli Palearo Fratino.
-----------------------------------------------------------------------------------------------------------------------------The research analyzes the design of the bulwarks in the work of the Palearo Fratino brothers,
military engineers in the service of Spain in the second half of the sixteenth century and is
structured in three main phases: the first analyzes the design of the bastion during the sixteenth
century, the second examines the design work of Jacopo and Giorgio Palearo in the Mediterranean
and especially in Sardinia, while the third proposed (through the use of results from the first two
phases of research and with the support of the data offered by the post-medieval archaeological
research) digital models of projects planned and not completed or no longer exist structures in the
fortified town of Alghero. The research method adopted in the analysis is graphical tool hearing,
able to provide relevant information and results to support historical and archaeological
investigation. The analysis of the military treatise is directed in particular to “Della fortificatione
delle città” of Maggi and Castriotto, cited by Jacopo Palearo as a reference text in the design of the
bulwarks of Cagliari. Projects analyzes, and the relief of some sections of representative works, has
identified a repertoire that highlighted the use (through the use of constructive solutions and
recurring patterns in relation to the existing and adapted to the site) of the treaty of Maggi and
Castriotto to confirm what was stated by El fratin. The data obtained from the treatises and works
have finally formed the basis for the development of digital models of the projects drawn up in the
period 1552-1578 for the construction of the fortifications of Alghero and allowed a better
understanding of the design of military engineers and of the project activity of the Palearo Fratino
brothers