The significance of space in James Joyce's Dubliners

openIn James Joyce's works space plays a pivotal role as a narrative device. This dissertation focuses on the spatial description in 'Dubliners', a collection of fifteen short stories set in the city of Dublin. The representation of space, both private and public, does not merely describe the physical element. Instead, it reveals details about the characters' self perception and identity whose close connection to the urban environment puts them in a state of paralysis. Elements of stillness and circularity establish the urban setting as an enclosing space which characters attempt to escape but are ultimately unable to. Chapter one offers a brief overview of different theories and studies regarding the notion of space as a literary device. In particular, this chapter focuses on the definition of chronotope which describes a subject's relationship with the physical element from both a psychological and phenomenological stem point. Chapter two aims at contextualising literature of space within European and, more specifically, Irish Modernism focusing on how 19th century colonialism and urbanization have shaped the perception and representation of space within literary works. Chapter three pertains to the analysis of space in the Dubliners tales, focusing on the characters' experience of the urban background: the journeys they take across the city, their unique approach to both private and public spaces and how this gives away crucial details about the author's own view and perception of Dubli

Modeling Cardiovascular Diseases with hiPSC-Derived Cardiomyocytes in 2D and 3D Cultures

In the last decade, the generation of cardiac disease models based on human-induced pluripotent stem cells (hiPSCs) has become of common use, providing new opportunities to overcome the lack of appropriate cardiac models. Although much progress has been made toward the generation of hiPSC-derived cardiomyocytes (hiPS-CMs), several lines of evidence indicate that two-dimensional (2D) cell culturing presents significant limitations, including hiPS-CMs immaturity and the absence of interaction between dierent cell types and the extracellular matrix. More recently, new advances in bioengineering and co-culture systems have allowed the generation of three-dimensional (3D) constructs based on hiPSC-derived cells. Within these systems, biochemical and physical stimuli influence the maturation of hiPS-CMs, which can show structural and functional properties more similar to those present in adult cardiomyocytes. In this review, we describe the latest advances in 2D- and 3D-hiPSC technology for cardiac disease mechanisms investigation, drug development, and therapeutic studies

Identification of a novel gene involved in Arrhythmogenic Right Ventricular Cardiomyopathy/Dysplasia

Arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D) is a genetic cardiac disease inherited as an autosomal dominant trait with incomplete penetrance and variable expressivity. Its main feature is the progressive substitution of the myocardium with fatty or fibro-fatty tissue, involving predominantly the right ventricle. Clinically, ARVC/D is characterized by ventricular arrhythmias, often associated with syncope and sudden cardiac death, especially in the young and athletes. Up to now, several disease genes have been identified, including 5 encoding desmosomal proteins. In this study, mutation screening for desmosomal genes performed in 80 consecutive unrelated Italian probands failed to detect mutation in about half of index cases, thus suggesting further genetic heterogeneity. On the basis of alphaT-catenin (a protein of cardiac area composita) cellular localization and function, mutation screening was then performed in CTNNA3 candidate gene in 76 affected subjects, negative for mutations in desmosomal genes. Four mutations have been detected. In vitro functional studies assessed the pathogenicity for two of them. For the first time mutations in CTNNA3 have been detected in a human disease. Particularly, the recurrence of pathogenic mutations in CTNNA3 gene in ARVC/D patients expands the concept of this disease beyond desmosomesLa cardiomiopatia aritmogena del ventricolo destro (ARVC/D) è una malattia genetica cardiaca, ereditata come carattere autosomico dominante a penetranza incompleta ed espressività variabile. La sua caratteristica principale è la progressiva sostituzione del miocardio del ventricolo destro con tessuto adiposo e/o fibroadiposo, con formazione di circuiti anatomici di rientro e conseguenti aritmie e morte improvvisa, specie nei giovani. Attualmente sono noti dieci geni malattia, di cui cinque sono codificanti per le proteine desmosomali. In questo studio, lo screening di mutazioni nei geni desmosomali eseguito in 80 pazienti affetti non ha evidenziato mutazioni in circa la metà dei casi, suggerendo la presenza di ulteriore eterogeneità genetica. In virtù della funzione e della localizzazione cellulare dell’alphaT-catenina (proteina dell’area composita), è stato svolto lo screening di mutazioni nel gene candidato CTNNA3 in 76 casi indice negativi per mutazioni nei geni desmosomali. Sono state identificate quattro variazioni. Studi funzionali in vitro hanno dimostrato la patogenicità per due di esse. Per la prima volta, mutazioni nel gene CTNNA3 sono state associate a una malattia umana. In particolare, la ricorrenza di mutazioni patogene nel gene CTNNA3 in pazienti ARVC/D estende il concetto di questa malattia oltre i desmosom

MicroRNAs in Cardiac Diseases

Since their discovery 20 years ago, microRNAs have been related to posttranscriptional regulation of gene expression in major cardiac physiological and pathological processes. We know now that cardiac muscle phenotypes are tightly regulated by multiple noncoding RNA species to maintain cardiac homeostasis. Upon stress or various pathological conditions, this class of non-coding RNAs has been found to modulate different cardiac pathological conditions, such as contractility, arrhythmia, myocardial infarction, hypertrophy, and inherited cardiomyopathies. This review summarizes and updates microRNAs playing a role in the different processes underlying the pathogenic phenotypes of cardiac muscle and highlights their potential role as disease biomarkers and therapeutic targets

Epigenetics and microRNAs in cardiovascular diseases

Cardiovascular diseases are among the leading causes of mortality worldwide. Besides environmental and genetic changes, these disorders can be influenced by processes which do not affect DNA sequence yet still play an important role in gene expression and which can be inherited. These so-called 'epigenetic' changes include DNA methylation, histone modifications, and ATP-dependent chromatin remodeling enzymes, which influence chromatin remodeling and gene expression. Next to these, microRNAs are non-coding RNA molecules that silence genes post-transcriptionally. Both epigenetic factors and microRNAs are known to influence cardiac development and homeostasis, in an individual fashion but also in a complex regulatory network. In this review, we will discuss how epigenetic factors and microRNAs interact with each other and how together they can influence cardiovascular diseases

Genetics meets epigenetics: Genetic variants that modulate noncoding RNA in cardiovascular diseases

After the recent description of the human genome by the ENCODE and the FANTOM consortia, major attention has been addressed to the so-called "genomic noise", which mainly consists of noncoding RNAs (ncRNAs). Among them, microRNAs and long non-coding RNAs have been demonstrated to modulate gene expression and to be involved in several human diseases. Since ncRNAs and their targets are encoded in the genome, genetic principles apply. Common variants are supposed to influence the expression level and the functionality of ncRNAs, with subsequent differential regulation of their target genes. Moreover, several reports showed that polymorphisms in ncRNA or their target genes play a role in the development of cardiovascular adverse phenotype. Here, we provide an overview of the effects of these variations in cardiovascular diseases