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X-ray absorption spectroscopy: a powerful tool for structural studies of molecules involved in the pathogenesis of neurodegenerative diseases
Full text linkQuesta tesi descrive l’applicazione della spettroscopia di assorbimento dei raggi X allo studio di sistemi biologici che sono particolarmente interessanti per la loro rilevanza biomedica.
Si usa una combinazione della XAS e di altre tecniche sperimentali per studiare tre classi di molecole (i peptidi Aβ, la proteina prionica e la neuromelanina) coinvolte nella patogenesi delle malattie neurodegenerative.
I peptidi Aβ sono la principale componente delle placche amiloidi, che costituiscono una delle lesioni caratteristiche osservate nel cervello dei malati di Alzheimer. È stato osservato che le placche amiloidi contengono elevate concentrazioni di ioni metallici quali Cu e Zn. Si effettuano misure di densità ottica, di spettroscopia infrarossa in trasformata di Fourier e di XAS per determinare la struttura atomica locale dei siti di legame dei metalli. Gli esperimenti mostrano che Cu e Zn hanno ruoli diversi nel processo di aggregazione, ed in particolare che lo Zn è più efficace del Cu nel promuoverla.
La proteina prionica è coinvolta nella patogenesi di una classe di malattie neurodegenerative infettive. In particolare, la conversione di questa proteina dalla sua forma normale alla cosiddetta forma scrapie causa l’enecefalopatia spongiforme trasmissibile. Si è osservato che la regione N-terminale della proteina prionica ha un’elevata affinità per metalli quali Cu e Zn. Gli esperimenti XAS descritti in questa tesi mostrano che il modo di coordinazione del Cu dipende dalla presenza di ioni Zn e che, pur non essendo lo Zn in grado di rimuovere il Cu legato alla proteina, è in grado di modificarne il modo di coordinazione.
La neuromelanina è una molecola che si accumula nei neuroni soggetti a processi neurodegenerativi nelle persone affette dalla malattia di Parkinson. La XAS è qui utilizzata per studiare la coordinazione dello zolfo nella neuromelanina umana, in alcune melanine sintetiche ed in due composti modello contenenti zolfo, la cisteina ed il tricocromo C. Sulla base di fit della neuromelanina umana e delle melanine sintetiche in termini dei composti modello, si riconosce la presenza di modi di coordinazione dello zolfo simili a quelli sia della cisteina, sia del tricocromo, e si quantifica la loro abbondanza relativa.
Infine, la XAS è utilizzata per studiare un problema non connesso alla patogenesi di una malattia neurodegenerativa, ovvero la mancanza di prolidasi. La prolidasi umana è un enzima importante nelle fasi finali del metabolismo delle proteine, e la sua carenza o il suo mancato funzionamento sono alla base di una grave malattia. Nel presente tesi si usa la XAS per determinare il sito di legame di Mn e Zn, mostrando la presenza di un sito di legame dimetallico nella forma attiva della proteina.This thesis describes the application of the X-ray Absorption Spectroscopy (XAS) to the study of biological systems that are particularly interesting for their biomedical role.
Three classes of molecules, namely the Aβ peptides, the prion protein and the neuromelanin, which are related to the pathogenesis of neurodegenerative diseases, are studied by using a combination of XAS and other experimental techniques.
Aβ peptides aggregates are the main component of the amyloid plaques, which are a peculiar lesion found in Alzheimer’s disease brains. The plaques have been shown to contain increased concentration of transition metals like Cu and Zn. Sedimentation assays, Fourier Transform Infrared Spectroscopy and XAS are used to determine the atomic structure around the metal binding site in samples where Aβ peptides are in complex with either Cu or Zn ions. The experiments show that Cu and Zn play different roles, and that Zn is more effective than Cu in promoting peptides aggregation.
The prion protein is related to the pathogenesis of a class of infectious, neurodegenerative diseases. In particular, the conversion of the prion protein from its normal cellular form to the so-called scrapie form is responsible for the transmissible spongiform encephalopathies, and it has been shown that the prion protein is able to bind Cu and Zn ions in its N-terminal octarepeat domain. The XAS experiments reported in this thesis show that the Cu binding mode depends on the presence of Zn ions and, even if Zn is not able to displace Cu, Zn is able to change the way Cu is bound to the prion protein.
Neuromelanin is a complex molecule accumulating in the neurons that undergo a degenerative process in Parkinson’s Disease. XAS is employed to investigate the sulphur binding mode in natural human neuromelanin, in synthetic melanins and in certain structurally known model compounds, namely cysteine and trichochrome C. Based on comparative fits of human and synthetic neuromelanin spectra in terms of those of model compounds, the occurrence of both cysteine- and trichochrome-like sulphur coordination modes is recognized and the relative abundance of these two types of structural arrangement is determined.
Finally, XAS is used to study a biomedical problem not connected to neurodegenerative diseases, that is the prolidase deficiency. Human prolidase is a metalloenzyme that is important in the latest stages of protein catabolism. XAS is employed here to obtain a structural characterization of the Mn and Zn binding sites and shows the existence of heterogeneous dimeric metallic sites in the active form of the protein
The Role of Metals in Misfolding and Aggregation Processes: X-ray Spectroscopy and Numerical Simulations
Full text linkThe role of metals in amyloid aggregation: A test case for ab initio simulations
No full textFirst principle ab initio molecular dynamics simulations of the Car-Parrinello type have proved to be of invaluable help in understanding the microscopic mechanisms of chemical bonding both in solid state physics and in structural biophysics. In this work we present as test cases the study of the Cu coordination mode in two especially important examples: Prion protein and beta-amyloids. Using medium size PC-clusters as well as larger parallel platforms, we are able to deal with systems comprising 300 to 500 atoms and 1000 to 1500 electrons for as long as 2 - 3 ps. We present structural results which confirm indications coming from NMR and XAS data
Going Beyond Counting First Authors in Author Co-citation Analysis
Full text linkThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Variations on the Author
Full text link“Variations on the Author” discusses two of Eduardo Coutinho’s recent films (Um Dia na Vida, from 2010, and Últimas Conversas, posthumously released in 2015) and their contribution to the general question of documentary authorship. The director’s filmography is characterized by a consistent yet self-effacing form of authorial self-inscription: Coutinho often features as an interviewer that rather than express opinions propels discourses; an interviewer that is good at listening. This mode of self-inscription characterizes him as an author who is not expressive but who is nonetheless markedly present on the screen. In Um Dia na Vida, however, Coutinho is completely absent form the image, while Últimas Conversas, on the contrary, includes a confessional prologue that moves the director from the margins to the center of his films. This article examines the ways in which these works stand out in the filmography of a director who offers new insights into the notion of cinematic authorship
Appropriate Similarity Measures for Author Cocitation Analysis
Full text linkWe provide a number of new insights into the methodological discussion about author cocitation analysis. We first argue that the use of the Pearson correlation for measuring the similarity between authors’ cocitation profiles is not very satisfactory. We then discuss what kind of similarity measures may be used as an alternative to the Pearson correlation. We consider three similarity measures in particular. One is the well-known cosine. The other two similarity measures have not been used before in the bibliometric literature. Finally, we show by means of an example that our findings have a high practical relevance.information science;Pearson correlation;cosine;similarity measure;author cocitation analysis
Dispelling the Myths Behind First-author Citation Counts
Full text linkWe conducted a full-scale evaluative citation analysis study of scholars in the XML research field to explore just how different from each other author rankings resulting from different citation counting methods actually are, and to demonstrate the capability of emerging data and tools on the Web in supporting more realistic citation counting methods. Our results contest some common arguments for the continued
use of first-author citation counts in the evaluation of scholars, such as high correlations between author rankings by first-author citation counts and other citation
counting methods, and high costs of using more realistic citation counting methods that are not well-supported by the ISI databases. It is argued that increasingly available digital full text research papers make it possible for citation analysis studies to go beyond what the ISI databases have directly supported and to employ more
sophisticated methods
The role of metals in protein conformational disorders - The case of prion protein and Aβ -peptide
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