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Identification and development of novel Inhibitors of viral polymerases: An In-silico Approach
Get PDFOur ability to answer some of the most fundamental questions of drug development process, such as how
proteins undergo conformational changes to bind a ligand, what are key protein residues which play pivotal
role for the binding, why a compound is active or inactive, or how its activity might be improved, how protein
dynamics is changed on introduction of resistant mutations, how resistant mutations render protein resistant
against inhibitors, what the mechanism of resistance changes in the binding free energy of a particular drug
candidate or the mechanisms and energetic consequences of conformational changes in a protein etc, is
limited often by our inability to appropriately catch dynamic features, including interactions with the solvent,
in a crystallographic structure which is just an average structure and thus lacks dynamics.
Here is where various biophysics based computational techniques come to our rescue, which provide huge
wealth of information related to protein dynamics and proteinligand
recognition. These methods have grown
in their effectiveness because of advances in algorithms, representations, and mathematical procedures for
studying such processes and are in the position of providing improved understanding of the basic science, the
biological events and molecular interactions that define a target for therapeutic intervention. However, the
approximations introduced in the computational approaches at different levels make a single technique in
many cases inappropriate to tackle the dauntingly complex problems related to the drug design. Thus, a
continuous feedback with experiments is required but also the appropriate combination of different
computational strategies might be helpful.
This work represents the application of computational techniques, such as docking, molecular dynamics,
algorithms to calculate free energy of binding of ligands into the binding pocket ( MMPBSA)
and algorithms
to study rare events (like unbinding of ligand from the binding site, Metadynamics, etc.) 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 and undocking path and to calculate binding energetics.
In this thesis, polymerases of three positive strand RNA viruses, viz, Hepatitis C Virus (HCV), Bovine Viral
Diarrhea Virus (BVDV) and Human Immunodeficiency Virus (HIV) have been targeted with an aim to come
out with more potent antivirals effective against wide range of resistant mutations. These viruses have created
havoc by effecting Human race directly or indirectly and thereby creating an urgent need for further
refinement and new development of antivirals drugs. Herein, plethora of computational techniques has been
applied on the three protein systems to answer fundamental questions of drug resistance, drug inhibition and
providing clues for improvement of antivirals
La minoranza vietnamita in Cambogia durante il processo di unificazione dell’Indocina (1887 - 1930)
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Diffusione e divulgazione della scienza: il caso della matematica
Get PDFLa tesi ha preso in esame i diversi rapporti e posizioni assunte dai ricercatori inglesi (‘85-‘00) e dal Consiglio di Lisbona (‘00) per affrontare la scarsa alfabetizzazione riscontrata presso il grande pubblico. Questo studio ha collocato, come ipotesi di partenza, la divulgazione fra l’apprendimento informale e non formale e ha assunto inesistente un quadro teorico atto a predire e descrivere il fenomeno divulgativo.
Si è cercato di delineare ciò che ha caratterizzato la sua nascita della divulgazione scientifica che diventa fenomeno sociale a partire dagli anni novanta del 1900. Sono stati oggetto di studio alcuni scenari e contesti di divulgazione, con particolare riferimento alla Matematica: Musei permanenti, Siti Web, Festival della Scienza e della Matematica, Mostre temporanee. Nello studio di caso sono prese in esame le interazioni tra divulgatore e diversi pubblici: la Lectio Magistralis di U. Eco (Festival della Matematica, Roma ‘08), una esperienza laboratoriale di due classi della Scuola Primaria (Festival della Scienza, Cagliari ‘09) e il punto di vista dei visitatori ad alla mostra temporanea Do you play Mathematics (Cagliari ‘09). Nonostante il proliferare dei più svariati scenari di divulgazione scientifica ancora oggi la non ha raggiunto il grande pubblico. Il superamento di questa cristallizzazione è data dall’interazione tra i due ambiti, divulgativo e scolastico. Il lavoro di tesi fornisce alcuni esempi su come tali ambiti possano incontrarsi e rinforzarsi per favorire e sviluppare la costruzione delle conoscenze scientifiche e più in generale la formazione dell’alunno come cittadino e parte del grande pubblico.
----------------------------------------------------------------------------------------------------------------------------------This thesis has examined the different relations and positions assumed by english researchers (‘85-‘00) and by the Council of Lisbon (‘00) in the face of the insufficient schooling present in most of the population. As a starting hypothesis, this study has placed the spread of the science between informal and formal learning and has assumed that a theoretical context able to predict and describe this phenomenon does not exist. This analysis has tried to outline what distinguished the beginning of the scientific spread that became a social phenomenon in the nineties of the nineteen hundred. Some cases and contexts of this spread, with particular reference to Mathematics, became the subject of study: permanent Museums, Web Sites, Science and Maths Festivals, temporary Exhibitions. In case studies the interaction between the spreader and his different publics has been considered: the Lectio Magistralis by U. Eco (Maths Festival, Rome ‘08), a workshop experience of two classes of the Primary School (Science Festival, Cagliari ‘09) and the point of view of visitors to the temporary exhibition Do you play Mathematics, (Cagliari ‘09). Despite the increase in the number of different ways that the science is promoted, the scientific knowledge has still not reached the great public even today. To overcome this problem, an interaction between the two fields, that of spreading and that of education, is necessary. This thesis provides some examples of how these fields can meet and become stronger in order to foster the development of scientific knowledge and on the whole, the education of the student as a citizen and part of the larger public
Fatty acid ethanolamides pinpoint nicotinic receptors and modulate neuronal excitability through nuclear receptor PPARα
No full textSPECIFIC AIMS OF THE STUDY
1) To investigate whether FAEs can suppress nicotine-induced stimulation of VTA dopamine
(DA) neuron firing rate through the peroxisome-proliferator-activated receptor-α (PPARα)
and to elucidate their mechanism of action in an in vitro brain slice preparation.
2) To determine whether there is an interaction between PPARα and nAChRs in VTA DA
cells: particularly, to characterize the postsynaptic effects of PPARα modulation on VTA
DA neurons, and to examine the contribution of nAChRs in the effects.
3) To study whether PPARα modulation of nAChRs in VTA DA neurons might confer DA
cells to access distinct firing patterns and/or to change their firing frequency both in vivo
and in vitro.
4) To examine the physiological relevance of PPARα modulation of nAChR stimulation
through behavioral analysis
A Country for Old Men? An Analysis of the Determinants of Long-Term Home Care in Europe
Get PDFThis paper investigates long-term home care utilisation in Europe. Data from SHARE on formal (nursing care or paid domestic help) and informal care (support provided by relatives) are used to study the probability and the quantity of both types of care being received. The overall process is framed in a fully simultaneous equation system which takes the form of a bivariate two-part model. Endogeneity and unobservable heterogeneity are addressed using a common latent factors approach. Age, disability and proximity-to-death are found to be important joint predictors of home care utilisation. The relationship between formal and informal care is small in absolute size and moves from substitutability to complementarity depending on the type of formal care considered
