Lähteiden lumoamat : Henry Biaudet, Liisi Karttunen ja suomalainen historiantutkimus Roomassa 1900-luvun alussa

Enchanted by Sources. Henry Biaudet, Liisi Karttunen and Finnish Historical Research in Rome in the Early Twentieth Century This study traces the scholarly endeavours of Henry Biaudet (1870 1915) and Liisi Karttunen (1880 1957) and "La mission historique finlandaise à Rome" which they founded in 1909. They are forgotten in Finnish historiography, but remain internationally renowned for their contribution to the nunciature studies. By investigating their historical work on the Counter- Reformation era, their roles in the scientific communities of Helsinki and Rome as well as the intersection of politics and science in their scholarly practices the study explores the nature of historical research in general at the turn of the twentieth century. The work covers fields such as historiography, university history and the political use of history. Methodologically the research is based on the analysis and contextualization of published and unpublished sources (e.g. correspondences, university records, scholarly publications and reviews in academic journals). Henry Biaudet criticized the previous research on the Nordic Counter-Reformation for its narrow national scope and sources. He sought out a new approach, including the use of sources in archives all over Europe and the inclusion of the Catholic viewpoint. Accordingly, Biaudet and Karttunen searched for records in archives in Southern Europe. Their unorthodox interpretations were denounced in Finland since the picture they gave of late sixteenth-century Sweden was too different from the national narrative. Moreover, Finnish national identity was firmly rooted in Protestantism, and questioning the benevolence of the Reformation and its main actors was considered as an attack not only against historical truth but also national values. The comparison between Biaudet s and Karttunen s arguments and the accepted narrative in Finland shows how traditional interpretations of the Nordic Reformation were influenced by the Lutheran ethos and European anticlerical rhetoric. Historians have recently paid substantial attention to the political use of history, usually focusing on politicized constructions of the national past. This study shows how research that met the criteria of modern historiography also served political purposes. Conducting research in an international community of historians and publishing ambitious scholarly studies that interested an international audience were ways to create a positive image of Finland abroad. These were not uniquely Finnish ideas but rather ideas shared by the international community of historians in Rome. In this context, scientific pursuits were given a clear political meaning. This enhances our understanding of nineteenth-century historiography being firmly rooted between science and politics.

Molecular Mechanisms of Androgen Receptor Interactions

The androgen receptor (AR) mediates the effects of the male sex-steroid hormones (androgens), testosterone and 5?-dihydrotestosterone. Androgens are critical in the development and maintenance of male sexual characteristics. AR is a member of the steroid receptor ligand-inducible transcription factor family. The steroid receptor family is a subgroup of the nuclear receptor superfamily that also includes receptors for the active forms of vitamin A, vitamin D3, and thyroid hormones. Like all nuclear receptors, AR has a conserved modular structure consisting of a non-conserved amino-terminal domain (NTD), containing the intrinsic activation function 1, a highly conserved DNA-binding domain, and a conserved ligand-binding domain (LBD) that harbors the activation function 2. Each of these domains plays an important role in receptor function and signaling, either via intra- and inter-receptor interactions, interactions with specific DNA sequences, termed hormone response elements, or via functional interactions with domain-specific proteins, termed coregulators (coactivators and corepressors). Upon binding androgens, AR acquires a new conformational state, translocates to the nucleus, binds to androgen response elements, homodimerizes and recruits sequence-specific coregulatory factors and the basal transcription machinery. This set of events is required to activate gene transcription (expression). Gene transcription is a strictly modulated process that governs cell growth, cell homeostasis, cell function and cell death. Disruptions of AR transcriptional activity caused by receptor mutations and/or altered coregulator interactions are linked to a wide spectrum of androgen insensitivity syndromes, and to the pathogenesis of prostate cancer (CaP). The treatment of CaP usually involves androgen depletion therapy (ADT). ADT achieves significant clinical responses during the early stages of the disease. However, under the selective pressure of androgen withdrawal, androgen-dependent CaP can progress to an androgen-independent CaP. Androgen-independent CaP is invariably a more aggressive and untreatable form of the disease. Advancing our understanding of the molecular mechanisms behind the switch in androgen-dependency would improve our success of treating CaP and other AR related illnesses. This study evaluates how clinically identified AR mutations affect the receptor s transcriptional activity. We reveal that a potential molecular abnormality in androgen insensitivity syndrome and CaP patients is caused by disruptions of the important intra-receptor NTD/LBD interaction. We demonstrate that the same AR LBD mutations can also disrupt the recruitment of the p160 coactivator protein GRIP1. Our investigations reveal that 30% of patients with advanced, untreated local CaP have somatic mutations that may lead to increases in AR activity. We report that somatic mutations that activate AR may lead to early relapse in ADT. Our results demonstrate that the types of ADT a CaP patient receives may cause a clustering of mutations to a particular region of the receptor. Furthermore, the mutations that arise before and during ADT do not always result in a receptor that is more active, indicating that coregulator interactions play a pivotal role in the progression of androgen-independent CaP. To improve CaP therapy, it is necessary to identify critical coregulators of AR. We screened a HeLa cell cDNA library and identified small carboxyl-terminal domain phosphatase 2 (SCP2). SCP2 is a protein phosphatase that directly interacts with the AR NTD and represses AR activity. We demonstrated that reducing the endogenous cellular levels of SCP2 causes more AR to load on to the prostate specific antigen (PSA) gene promoter and enhancer regions. Additionally, under the same conditions, more RNA polymerase II was recruited to the PSA promoter region and overall there was an increase in androgen-dependent transcription of the PSA gene, revealing that SCP2 could play a role in the pathogenesis of CaP.