Tras comprobar en investigaciones preliminares relacionadas con el Trabajo de Final de Máster la ausencia de un estudio crítico completo y ordenado sobre el recurso a Heráclito en la obra de Friedrich Nietzsche, se evidenció la necesidad de desarrollar una investigación exhaustiva al respecto. La presente tesis doctoral atiende esta necesidad y contribuye en el campo de los estudios nietzscheanos con la aportación de un trabajo crítico en el que se presentan y analizan siguiendo el orden cronológico en que fueron escritos, todos los pasajes de las obras y los textos para las lecciones y conferencias impartidas por el autor que contienen alusiones a Heráclito. Cada uno de estos pasajes se ha contextualizado y comentado detalladamente, revisando las fuentes bibliográficas relacionadas y contrastándolo con las aportaciones más relevantes de la tradición interpretativa, tanto de los estudios nietzscheanos como de los heraclíteos, y aportando después nuestras propias consideraciones sobre el sentido del recurso en cada caso. Los comentarios de los diversos pasajes se complementan con el análisis de las alusiones a Heráclito contenidas en apuntes y fragmentos póstumos. También se revisan algunas cuestiones derivadas de la exploración, que suelen generar bastante confusión y a las que se ha dedicado un apartado específico que contribuye a mejorar su comprensión. Por último, en un documento anexo a la tesis doctoral se presenta la relación completa y cronológicamente ordenada de todas las citas, facilitando así una consulta rápida de los pasajes en cuestión, a la vez que una visión de conjunto del proceso de las citas a lo largo de toda la obra del autor, junto con la posibilidad de contrastar de manera directa las alusiones realizadas en las anotaciones de los póstumos, y en las obras y otros textos, en un mismo periodo cronológico. La presente investigación ofrece así un estudio completo, sistemático y cronológicamente ordenado del recurso a Heráclito en el conjunto de la obra del autor, con indicaciones precisas sobre el interés, sentido y contexto de cada una de las citas, que permite comprobar el alcance real de la cuestión a partir de la evidencia de los propios textos, ante la frecuente tendencia a utilizar las citas de manera aislada, superficial o incluso supeditada a determinados intereses interpretativos. / After checking in preliminary investigations, related to my Master Thesis, the absence of a full and orderly critical study on the use of Heraclitus in the work of Friedrich Nietzsche, we realized the need to develop a thorough investigation on the matter. This PhD thesis serves this need and contributes in the field of Nietzschean studies with a critical work that is presented and analysed according to the chronological order in which all the passages of the works and texts, for the lessons and lectures given by the author, containing allusions to Heraclitus, were written. Each of these passages has been contextualized and commented on in detail, reviewing related bibliographic sources and contrasting it with the most relevant contributions of the interpretive tradition, both for the Nietzschean studies and for those of Heraclitus, and then providing our own considerations on the meaning of the resource in each case. The comments of the various passages are complemented by the analysis of the allusions to Heraclitus contained in notes and posthumous fragments. In a document attached to the doctoral thesis I present a complete and chronologically ranked list of all the citations, thus facilitating a quick reference of the passages in question, as well as an overview of the processing of citations throughout the work of the author, along with the possibility to compare directly the allusions made in the annotations of the posthumous, and in the works and other texts, in a same chronological period. This research offers a full, systematic and chronologically ordered study on the reference to Heraclitus in all the work of the author, with precise indications on interest, meaning, and context of each one of the citations, allowing to show the real scope of the question from the evidence of the texts, in contrast with the frequent tendency to use citations in an isolated and superficial manner, or even subject to certain interpretive interests. I am also attaching an annex that addresses some issues arising from my exploration, which tend to create confusion, and to which a somewhat more detailed attention has been paid, helping to improve its understanding. / Dopo aver constatato negli studi preliminari relativi al Lavoro Finale di Master Fondamenti per un studio sull’influenza di Eraclito in Nietzsche l’assenza di uno studio critico completo e ordinato sui riferimenti ad Eraclito nell’opera di Nietzsche, si evidenziò la necessità di sviluppare un’investigazione esaustiva al riguardo. La presente tesi di dottorato soddisfa questa necessità e contribuisce nel campo degli studi nietzscheani con un lavoro critico nel quale si presentano e analizzano seguendo l’ordine cronologico in cui furono scritti, tutti i passi delle opere e i testi per le lezioni e conferenze tenute dall’autore che contengono allusioni a Eraclito. Ciascuno di questi passi è stato contestualizzato e commentato dettagliatamente, controllando le relative fonti bibliografiche ed è stato confrontato con i contributi più rilevanti della tradizione interpretativa, tanto degli studiosi nietzscheani come di quelli eraclitei. I commenti dei diversi passi si completano anche con l’analisi delle allusioni a Eraclito contenuti in appunti e frammenti postumi, e con le nostre considerazioni sul significato del riferimento, in ogni singolo caso. Sono trattate anche alcune questioni derivate dall’analisi, che solitamente generano abbastanza confusione, e alle quali si è dedicata un’attenzione un po’ più dettagliata che contribuisce a migliorarne la comprensione. In un documento annesso alla tesi di dottorato si presenta la relazione completa e cronologicamente ordinata di tutte le citazioni, facilitando così una consultazione rapida dei passi in questione, contemporaneamente ad una visione della totalità del processo di citazioni nell’arco di tutta l’opera dell’autore, insieme alla possibilità di confrontare in modo diretto le allusioni ad Eraclito nelle annotazioni dei frammenti postumi e nelle opere e in altri testi in uno stesso periodo cronologico. Il presente studio offre così un’analisi completa, sistematica e cronologicamente ordinata dei riferimenti a Eraclito nella totalità dell’opera di Nietzsche, con indicazioni precise sull’interesse, sul significato e sul contesto di ciascuna delle citazioni che permette così di confrontare l’importanza della questione a partire dall’evidenza dei testi stessi, di fronte alla frequente tendenza ad utilizzare le citazioni in maniera isolata, superficiale o perfino subordinata a particolari interessi interpretativi.

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Previous studies of genes associated with retroviral-induced neoplasia have provided the foundation for much of our current knowledge of both tumor suppressor and oncogenes, and have contributed to our understanding of both gene function and malignant transformation. The study of Friend virus-induced erythroleukemia, a well-studied example of multistage malignancy, has led to the identification of several oncogenes, including the Ets transcription factor, fli-1. Fli-1 plays a vital role in hematopoiesis, and vasculogenesis through the transcriptional regulation of its target genes, some of which are critical for the control of cellular proliferation, differentiation, and survival. The aberrant regulation of Fli-1 is associated with a number of cancers and human diseases, including erythroleukemia, Ewing’s sarcoma, lupus, and Jacobsen or Paris Trousseau syndrome. The essential goal set out to be achieved by the research presented herein is to establish a better understanding of both the oncogenic and developmental roles of Fli-1 by investigating the molecular basis by which its deregulated expression leads to fundamental aberration in the fine balance between proliferation and differentiation.

This thesis investigates the shaping of Christian social behavioural instructions by the author’s theological vision in 1 Peter. The notion that these instructions are de facto derived from the author’s theological conviction as his ultimate concern is more often assumed or neglected, than seriously considered in Petrine scholarship. This thesis aims at adding one more dimension to scholars’ discussion by seeking an empathic understanding of the Petrine mode of Christian social engagement from “an insider” perspective of the author’s own theological vision as his primary concern. Besides paying attention to the more obvious meaning and the literary features of the text, historical data of the socio-political background of 1 Peter are also employed as an entrance to understand imaginatively the author’s vision and the implications of his social ethics. In the exegetical study of the Petrine text with particular reference to the author’s extensive use of Old Testament language, Jesus Christ is shown to be underscored in 1 Peter as the Jewish expected Messiah but who has submitted to human suffering as a resident-alien on the cross. Christians are also perceived as “elect exiles of Diaspora” on earth inheriting the self-understanding and eschatological hope of the Jewish Diaspora. The Petrine social strategy of “differentiated resistance” is thus understood as a token of Christians’ solidarity with the Messiah Christ and a congruent behavioural expression of their identity as “elect exiles of Diaspora”. “Ultimate allegiance to God” is seen to be the overriding boundary of Christians’ accommodation to the pagan culture to ensure their remaining in the grace/salvation of God. In the historical study of the Jewish Diaspora’s social engagement, it is demonstrated that the Petrine appropriation to Christians of Jewish self-definitions includes the Jewish social strategy in the Diaspora which also reflected a form of “differentiated resistance”. Theological conviction as the primary consideration of the early Christians when formulating their social strategies is then further demonstrated by the comparison of 1 Peter with Revelation and the Epistle to Diognetus. The thesis concludes with a reflection on the continuing significance of 1 Peter to Christians’ social engagement in the modern world and on the possible cooperation between the theological approach and socio-historical approach to investigate biblical texts.

Bladder cancer is one of the commoner malignancies in humans and current treatments for invasive disease typically give a five year survival rate of around fifty percent. Current chemotherapeutic agents increase survival by a small amount; clearly there is the need for improved treatments and for this, novel targets need to be identified. One putative target is the Fos family member Fos-related antigen-1 (Fra-1), which form part of the AP-1 transcription factor complex. Fra-1 is elevated in numerous human malignancies and regulates the transcription of genes involved in many aspects of the malignant process, such as migration and invasion. Regulatory control of Fra-1 has been incompletely studied to date; it is known that MAP Kinase dependent signalling can influence Fra-1 accumulation but other aspects of control are only now being elucidated. This thesis demonstrates that Fra-1 is present in the majority of bladder cancers, that it is regulated by the structure of the C-terminus and MAP Kinase dependent phosphorylation of the amino acids Ser[superscript 252] and Ser[superscript 265], and undergoes proteasomal degradation. This highlights the potential role of Fra-1 as a novel therapeutic target and provides more information on the regulation of Fra-1 which may be targeted with novel agents.

Introduction: Interferon regulatory factor-7 (IRF-7), the “master regulator” of type 1 interferon, has shown to orchestrate anti-viral immune responses via fine-tuning expression of interferons and interferon-stimulated genes. Methods: IRF-7 levels were examined using multi-parametric flow-cytometry in HIV-uninfected Manitoban donors and in HIV-infected and HIV-uninfected Kenyan volunteers from a well-characterized Kenyan sex worker cohort. IRF-7 expression level was reduced by IRF-7 specific siRNA or shRNA encoded in lentivirus and administered into ex-vivo CD4+ T cells by transfection or transduction. Results: In unstimulated PBMC, IRF-7 was constitutively expressed at low levels in every defined subset we examined. We observed less HIV-infected cells (~10%) with IRF-7 knockdown, suggesting that IRF-7 may play a role in HIV infection. Conclusions: Unexpectedly, it was found that even though IRF-7 had been implicated in orchestrating antiviral events, reducing IRF-7 expression in ex vivo CD4+ T cells did not increase the cellular susceptibility to productive HIV infection. / February 2017