Conformational dynamics in microRNAs : the example of miR-34a targeting Sirt1 mRNA

In biology, regulatory mechanisms are essential to achieve complex tasks, as virtually every process can be positively or negatively modulated in its outcome, upon different cues. In humans, microRNAs (miRNAs) constitute a fundamental layer of post-transcriptional gene expression regulation. This class of molecules finely tune protein expression, by downregulating messenger RNAs (mRNA) levels and their translation. The mechanism by which miRNAs find and act upon their targets primarily relies on their nucleotide sequence, relative to the corresponding binding site on the mRNA. The development of an exhaustive miRNA–mRNA interactome is particularly attractive because of the profound implication for basic biology as well as for diagnostics and therapeutics in human health. However, computational prediction of target sites and associated downregulation levels, using the limited sequence determinants available, is still an outstanding challenge in the field. In this thesis, we bring forward the hypothesis that modeling of miRNA–mRNA pairs might benefit from considering the inherent structural flexibility of these complexes, at the molecular level. In the introductory chapter, we present the structural features of RNAs with a focus on their conformational dynamics and NMR spectroscopy as a tool to investigate these motions. The molecular details of miRNA biogenesis and function are later introduced to contextualize the results of Paper I. Finally, the challenges associated with RNA sample preparation are discussed in light of the work presented in Paper II. In Paper I, we show that a miRNA–mRNA pair involved in a cancer-regulating pathway exploits its flexibility to toggle between lower and higher target repression states. This study shows that suboptimal structures of a given miRNA–mRNA pair, that are overlooked by computational prediction and that often elude experimental detection, can be functionally relevant and are essential to draw a mechanistic picture of miRNA function. The methods used in Paper I for RNA sample preparation and molecular simulation are described in Paper II and II, respectively. While these methods were essential to achieve the results of Paper I, they also find widespread application in the RNA field

Oli essenziali nell'otite da malassezia pachydermatis nel cane e nel gatto: saggi in vitro e in vivo

La tesi si è occupata dell'otite da Malassezia pachydermatis nel cane e nel gatto arrivando a conclusione che oli essenziali sono una valida alternativa al trattamento convenzionale della patologia

Sistemazione idraulica del bacino del canale Ozzoretto (LU)

La tesi si colloca nella tematica della difesa del suolo. In breve si può dire che il canale Ozzoretto fa parte di un sistema piuttosto complesso, essendo un affluente del canale Ozzeri. Sul territorio di Lucca sono previsti, ed in parte realizzati, una serie di interventi per la regimazione completa di detto sistema; in particolare gli interventi sugli affluenti hanno lo scopo di ridurre le portate in ingresso al canale principale o contenere le acque che temporaneamente non possono scolarvi a causa dei livelli liquidi. La tesi si articola in due macro-parti: lo studio idrologico a supporto della sistemazione (grazie al quale si è dimostrato che le dimensioni del canale, allo stato attuale, sono completamente insufficienti a contenere le portate duecentennali) e la sistemazione vera e propria con la individuazione e progettazione degli interventi necessari. Per raggiungere l’obiettivo è stato necessario arginare la porzione valliva del canale Ozzoretto e realizzare due casse di espansione in derivazione; per sistemare la porzione di monte si sono previste e progettate tre casse di espansione in linea e la risagomatura di alcune sezioni; inoltre, per trovare la miglior soluzione dal punto di vista tecnico-economico, sono state valutate altre ipotesi progettuali (diversivi e raddoppi), poi scartate. Infine per completare lo studio si sono dimensionati e verificati i dettagli costruttivi ed è stata eseguita la stima dei costi

Characterizations of inner product spaces by orthogonal vectors

LetXbe a real normed space with unit closed ballB. We prove thatXis an inner product space if and only if it is true that wheneverx,yare points in?Bsuch that the line throughxandysupports22Bthenx?yin the sense of Birkhoff

Increasing sequences of sets and preservation of properties

We deal with increasing sequences of sets: by considering sequences of sets in a given class, we study when the closure of the union belongs to the same class. We consider here several classes of bounded, closed convex sets

The size of a Minkowski ellipse that contains the unit ball

In this paper we study the minimum radius of Minkowski ellipses (with antipodal foci on the unit sphere) necessary to contain the unit ball of a (normed or) Minkowski plane. We obtain a general upper bound depending on the modulus of convexity, and in the special case of a so-called symmetric Minkowski plane (a notion that we will recall in the paper) we prove a lower bound, and also we obtain that 3 is the exact upper boun

Increasing sequences of sets and preservation of properties

We deal with increasing sequences of sets: we study when, by considering sequences of sets in a given class, the closure of the union is a set in the same class. We consider here several classes of bounded, closed convex sets

Parameters in Banach spaces and orthogonality

In Banach spaces, plenty of parameters have been considered: they are often dened by using pairs of vectors. Rarely they are dened by considering pairs of vectors which are orthogonal in the sense of Birkho and James; in that case the study is often not easy. In fact, it can be dicult to identify pairs of orthogonal vectors; so to calculate the value of these parameters, to compare them with the other parameters, to see if they have some stability with respect to changes of the norm. In this paper we shall do this for a couple of new parameters. Keywords: Orthogona