Molecular studies on LIM-domain protein CRP1

Various intrinsic and external factors are constantly attacking the cells causing damage to DNA and to other cellular structures. Cells in turn have evolved with different kinds of mechanisms to protect against the attacks and to repair the damage. Ultraviolet radiation (UVR) is one of the major environmental genotoxic carcinogens that causes inflammation, mutations, immunosuppression, accelerated aging of the skin and skin cancers. Epidermis is the outermost layer of the skin consisting mostly of keratinocytes, whose primary function is to protect the skin against e.g. UV radiation. LIM domain proteins are a group of proteins involved in regulation of cell growth, damage signalling, cell fate determination and signal transduction. Despite their two zinc fingers, LIM domains do not bind to DNA, but rather mediate protein-protein interactions and function as modular protein binding interfaces. We initially identified CSRP1 as UVR-regulated transcript by using expression profiling. Here we have further studied the regulation and function of CRP1, a representative of cysteine rich protein- family consisting of two LIM domains. We find that CRP1 is increased by UVR in primary human keratinocytes and in normal human skin fibroblasts. Ectopic expression of CRP1 protected the cells against UVR and provided a survival advantage, whereas silencing of CRP1 rendered the cells more photosensitive. Actinic keratosis is a premalignant lesion of skin caused by excess exposure to sunlight and sunburn, which may lead to formation of squamous cell carcinoma. The expression of CRP1 was increased in basal keratinocytes of Actinic keratosis patient specimens suggesting that CRP1 may be increased by constant exposure to UVR and may provide survival advantage for the cells also in vivo. In squamous cell carcinoma, CRP1 was only expressed in the fibroblasts surrounding the tumour. Moreover, we found that ectopic expression of CRP1 suppresses cell proliferation. Transforming growth factor beta (TGFbeta) is a multifunctional cytokine that regulates several functions in cell including growth, apoptosis and differentiation, and plays important roles in pathological disorders like cancer and fibrosis. We found that TGFbeta-signalling pathway regulates CRP1 at protein, but not at transcriptional level. The increase was mediated both through Smad and non-Smad signalling pathways involving MAPK/p38. Furthermore, we found that TGFbeta-mediated increase in CRP1 was associated with myofibroblast differentiation, and that CRP1 was significantly more expressed in idiopathic pulmonary fibrosis as compared to normal lung specimens. Since cell contractility is a distinct feature of myofibroblasts, and CRP1 is associated with actin cytoskeleton, we studied the role of CRP1 in cell contractility. CRP1 was found to localize to stress fibres that mediate contractility and to mediate myofibroblast contraction. These studies identify CRP1 as a stress responsive and cytokine regulated cytoskeletal protein that participates in pathological processes involved in fibrotic diseases and cancer.

The North in the Old English Orosius : A Geographical Narrative in Context

This doctoral dissertation examines the description of the North as it appears in the Old English Orosius (OE Or.) in the form of the travel accounts by Ohthere and Wulfstan and a catalogue of peoples of Germania. The description is discussed in the context of ancient and early medieval textual and cartographic descriptions of the North, with a special emphasis on Anglo-Saxon sources and the intellectual context of the reign of King Alfred (871-899). This is the first time that these sources, a multidisciplinary approach and secondary literature, also from Scandinavia and Finland, have been brought together. The discussion is source-based, and archaeological theories and geographical ideas are used to support the primary evidence. This study belongs to the disciplines of early medieval literature and (cultural) history, Anglo-Saxon studies, English philology, and historical geography. The OE Or. was probably part of Alfred s educational campaign, which conveyed royal ideology to the contemporary elite. The accounts and catalogue are original interpolations which represent a unique historical source for the Viking Age. They contain unparalleled information about peoples and places in Fennoscandia and the southern Baltic and sailing voyages to the White Sea, the Danish lands, and the Lower Vistula. The historical-philological analysis reveals an emphasis on wealth and property, rank, luxury goods, settlement patterns, and territorial divisions. Trade is strongly implied by the mentions of central places and northern products, such as walrus ivory. The references to such peoples as the Finnas, the Cwenas, and the Beormas appear in connection with information about geography and subsistence in the far North. Many of the topics in the accounts relate to Anglo-Saxon aristocratic culture and interests. The accounts focus on the areas associated with the Northmen, the Danes and the Este. These areas resonated in the Anglo-Saxon geographical imagination: they were curious about the northern margin of the world, their own continental ancestry and the geography of their homeland of Angeln, and they had an interest in the Goths and their connection with the southern Baltic in mythogeography. The non-judgemental representation of the North as generally peaceful and relatively normal place is related to Alfredian and Orosian ideas about the unity and spreading of Christendom, and to desires for unity among the Germani and for peace with the Vikings, who were settling in England. These intellectual contexts reflect the innovative and organizational forces of Alfred s reign. The description of the North in the OE Or. can be located in the context of the Anglo-Saxon worldview and geographical mindset. It mirrors the geographical curiosity expressed in other Anglo-Saxon sources, such as the poem Widsith and the Anglo-Saxon mappa mundi. The northern section of this early eleventh-century world map is analyzed in detail here for the first time. It is suggested that the section depicts the North Atlantic and the Scandinavian Peninsula. The survey of ancient and early medieval sources provides a comparative context for the OE Or. In this material, produced by such authors as Strabo, Pliny, Tacitus, Jordanes, and Rimbert, the significance of the North was related to the search for and definition of the northern edge of the world, universal accounts of the world, the northern homeland in the origin stories of the gentes, and Carolingian expansion and missionary activity. These frameworks were transmitted to Anglo-Saxon literary culture, where the North occurs in the context of the definition of Britain s place in the world.

Análisis de la preposición hacia y establecimiento de sus equivalentes en finés

Title of the Master's thesis: Análisis de la preposición hacia y establecimiento de sus equivalentes en finés (trans. Analysis of the Spanish preposition hacia and the finding of its equivalents in Finnish) Abstracts: The aim of this Master thesis is to provide a detailed analysis of the Spanish preposition hacia from a cognitive perspective and to establish its equivalents in Finnish language. In this sense, my purpose is to demonstrate the suitability of both cognitive perspectives and Contrastive Linguistics for semantic analysis. This thesis is divided into five chapters. The first chapter includes a presentation and a critical review of the monolingual lexical processing and semantic analysis of the Spanish preposition hacia in major reference works. Through this chapter it is possible to see both the inadequacies and omissions that are present in all the given definitions. In this sense, this chapter shows that these problems are not but the upper stage of an ontological (and therefore methodological) problem in the treatment of prepositions. The second chapter covers the presentation of the methodological and theoretical perspective adopted for this thesis for the monolingual analysis and definition of the Spanish preposition hacia, following mainly the guidelines established by G. Lakoff (1987) and R. Langacker (2008) in his Cognitive grammar. Taken together, and within the same paradigm, recent analytical and methodological contributions are discussed critically for the treatment of polysemy in language (cf. Tyler ja Evans 2003). In the third chapter, and in accordance with the requirements regarding the use of empirical data from corpora, is my aim to set out a monolingual original analysis of the Spanish preposition hacia in observance of the principles and the methodology spelled out in the second chapter. The main objective of this chapter is to build a full fledged semantic representation of the polysemy of this preposition in order to understand and articulate its meanings with Finnish language (and other possible languages). The fourth chapter, in accordance with the results of chapter 3, examines and describes and establishes the corresponding equivalents in Finnish for this preposition. The results obtained in this chapter are also contrasted with the current bilingual lexicographical definitions found in the most important dictionaries and grammars. Finally, in the fifth chapter of this thesis, the results of this work are discussed critically. In this way, some observations are given regarding both the ontological and theoretical assumptions as well regarding the methodological perspective adopted. I also present some notes for the construction of a general methodology for the semantic analysis of Spanish prepositions to be carried out in further investigations. El objetivo de este trabajo, que caracterizamos como una tarea de carácter comparativo-analítico, es brindar un análisis detallado de la preposición castellana hacia desde una perspectiva cognitiva en tanto y a través del establecimiento de sus equivalentes en finés. Se procura, de esta forma, demostrar la adecuación de una perspectiva cognitiva tanto para el examen como para el establecimiento y articulación de la serie de equivalentes que una partícula, en nuestro caso una preposición, encuentra en otra lengua. De esta forma, y frente a definiciones canónicas que advierten sobre la imposibilidad de una caracterización acabada del conjunto de usos de una preposición, se observa como posible, a través de la aplicación de una metodología teórica-analítica adecuada, la construcción de una definición viable tanto en un nivel jerárquico como descriptivo. La presente tesis se encuentra dividida en cinco capítulos. El primer capítulo comprende una exposición y revisión critica del tratamiento monolingüe lexicográfico y analítico que la preposición hacia ha recibido en las principales obras de referencia, donde se observa que las inadecuaciones y omisiones presentes en la totalidad de las definiciones analizadas representan tan sólo el estadio superior de una problemática de carácter ontológico y, por tanto, metodológico, en el tratamiento de las preposiciones. El capítulo segundo comprende la presentación de la perspectiva teórica metodológica adoptada en esta tesis para el análisis y definición monolingüe de la preposición hacia, teniendo por líneas directrices las propuestas realizadas por G. Lakoff , así como a los fundamentos establecidos por R. Langacker en su propuesta cognitiva para una nueva gramática. En forma conjunta y complementaria, y dentro del mismo paradigma, empleamos, discutimos críticamente y desarrollamos diferentes aportes analítico-metodológicos para el tratamiento de la polisemia en unidades lingüísticas locativas. En el capítulo tercero, y en acuerdo con las exigencias respecto a la utilización de datos empíricos obtenidos a partir de corpus textuales, se expone un análisis original monolingüe de la preposición hacia en observancia de los principios y la metodología explicitada en el capítulo segundo, teniendo por principal objetivo la construcción de una representación semántica de la polisemia de la preposición que comprenda y articule los sentidos prototípicos para ésta especificados. El capítulo cuarto, y en acuerdo con los resultados de nuestro análisis monolingual de la preposición, se examinan, describen y establecen los equivalentes correspondientes en finés para hacia; asimismo, se contrastan en este capítulo los resultados obtenidos con las definiciones lexicográficas bilingües vigentes. Se recogen en el último y quinto capítulo de esta tesis algunas observaciones tanto respecto a los postulados ontológicos y teórico-metodológicos de la perspectiva adoptada, así como algunas notas para la construcción de una metodología general para el análisis semántico preposicional.

Expected Performance of the ATLAS Experiment - Detector, Trigger and Physics

A detailed study is presented of the expected performance of the ATLAS detector. The reconstruction of tracks, leptons, photons, missing energy and jets is investigated, together with the performance of b-tagging and the trigger. The physics potential for a variety of interesting physics processes, within the Standard Model and beyond, is examined. The study comprises a series of notes based on simulations of the detector and physics processes, with particular emphasis given to the data expected from the first years of operation of the LHC at CERN.

Antarctic ice shelf melting and its impact on the global sea ice-ocean system

Earth s ice shelves are mainly located in Antarctica. They cover about 44% of the Antarctic coastline and are a salient feature of the continent. Antarctic ice shelf melting (AISM) removes heat from and inputs freshwater into the adjacent Southern Ocean. Although playing an important role in the global climate, AISM is one of the most important components currently absent in the IPCC climate model. In this study, AISM is introduced into a global sea ice-ocean climate model ORCA2-LIM, following the approach of Beckmann and Goosse (2003; BG03) for the thermodynamic interaction between the ice shelf and ocean. This forms the model ORCA2-LIM-ISP (ISP: ice shelf parameterization), in which not only all the major Antarctic ice shelves but also a number of minor ice shelves are included. Using these two models, ORCA2-LIM and ORCA2-LIM-ISP, the impact of addition of AISM and increasing AISM have been investigated. Using the ORCA2-LIM model, numerical experiments are performed to investigate the sensitivity of the polar sea ice cover and the Antarctic Circumpolar Current (ACC) transport through Drake Passage (DP) to the variations of three sea ice parameters, namely the thickness of newly formed ice in leads (h0), the compressive strength of ice (P*), and the turning angle in the oceanic boundary layer beneath sea ice (θ). It is found that the magnitudes of h0 and P* have little impact on the seasonal sea ice extent, but lead to large changes in the seasonal sea ice volume. The variation in turning angle has little impact on the sea ice extent and volume in the Arctic but tends to reduce them in the Antarctica when ignored. The magnitude of P* has the least impact on the DP transport, while the other two parameters have much larger influences. Numerical results from ORCA2-LIM and ORCA2-LIM-ISP are analyzed to investigate how the inclusion of AISM affects the representation of the Southern Ocean hydrography. Comparisons with data from the World Ocean Circulation Experiment (WOCE) show that the addition of AISM significantly improves the simulated hydrography. It not only warms and freshens the originally too cold and too saline bottom water (AABW), but also warms and enriches the salinity of the originally too cold and too fresh warm deep water (WDW). Addition of AISM also improves the simulated stratification. The close agreement between the simulation with AISM and the observations suggests that the applied parameterization is an adequate way to include the effect of AISM in a global sea ice-ocean climate model. We also investigate the models capability to represent the sea ice-ocean system in the North Atlantic Ocean and the Arctic regions. Our study shows both models (with and without AISM) can successfully reproduce the main features of the sea ice-ocean system. However, both tend to overestimate the ice flux through the Nares Strait, produce a lower temperature and salinity in the Hudson Bay, Baffin Bay and Davis Strait, and miss the deep convection in the Labrador Sea. These deficiencies are mainly attributed to the artificial enlargement of the Nares Strait in the model. In this study, the impact of increasing AISM on the global sea ice-ocean system is thoroughly investigated. This provides a first idea regarding changes induced by increasing AISM. It is shown that the impact of increasing AISM is global and most significant in the Southern Ocean. There, increasing AISM tends to freshen the surface water, to warm the intermediate and deep waters, and to freshen and warm the bottom water. In addition, increasing AISM also leads to changes in the mixed layer depths (MLD) in the deep convection sites in the Southern Ocean, deepening in the Antarctic continental shelf while shoaling in the ACC region. Furthermore, increasing AISM influences the current system in the Southern Ocean. It tends to weaken the ACC, and strengthen the Antarctic coastal current (ACoC) as well as the Weddell Gyre and the Ross Gyre. In addition to the ocean system, increasing AISM also has a notable impact on the Antarctic sea ice cover. Due to the cooling of seawater, sea ice concentration and thickness generally become higher. In austral winter, noticeable increases in sea ice concentration mainly take place near the ice edge. In regards with sea ice thickness, large increases are mainly found along the coast of the Weddell Sea, the Bellingshausen and Amundsen Seas, and the Ross Sea. The overall thickening of sea ice leads to a larger volume of sea ice in Antarctica. In the North Atlantic, increasing AISM leads to remarkable changes in temperature, salinity and density. The water generally becomes warmer, more saline and denser. The most significant warming occurs in the subsurface layer. In contrast, the maximum salinity increase is found at the surface. In addition, the MLD becomes larger along the Greenland-Scotland-Iceland ridge. Global teleconnections due to AISM are studied. The AISM signal is transported with the surface current: the additional freshwater from AISM tends to enhance the northward spreading of the surface water. As a result, more warm and saline water is transported from the tropical region to the North Atlantic Ocean, resulting in warming and salt enrichment there. It would take about 30 40 years to establish a systematic noticeable change in temperature, salinity and MLD in the North Atlantic Ocean according to this study. The changes in hydrography due to increasing AISM are compared with observations. Consistency suggests that increasing AISM is highly likely a major contributor to the recent observed changes in the Southern Ocean. In addition, the AISM might contribute to the salinity contrast between the North Atlantic and North Pacific, which is important for the global thermohaline circulation.

De "de" : Estudio histórico-comparativo de los usos y la semántica de la preposición "de" en español

El presente estudio supone un intento de describir y analizar el uso de la preposición "de" sobre la base de un corpus diacrónico, con énfasis en las diferentes relaciones semánticas que establece. Partiendo de un total de más de 16.000 casos de "de" hemos establecido 48 categorías de uso, que corresponden a cuatro tipos de construcción sintáctica, a saber, el uso de "de" como complemento de nombres (CN), verbos (CV), adjetivos (CA) y, finalmente, su uso como núcleo de expresiones adverbiales independientes (CI). El estudio consta de tres partes fundamentales. En la parte I, se introduce la Lingüística Cognitiva, que constituye la base teórica esencial del trabajo. Más exactamente, se introducen conceptos como la teoría del prototipo, la teoría de las metáforas conceptuales y la gramática cognitiva, especialmente las ideas de "punto de referencia" y "relación intrínseca" (Langacker 1995, 1999). La parte II incluye el análisis de las 48 categorías. En esta parte se presentan y comentan casi 2.000 ejemplos del uso contextual de "de" extraídos del corpus diacrónico. Los resultados más importantes del análisis pueden resumirse en los siguientes puntos: El uso de "de" sigue siendo esencialmente el mismo en la actualidad que hace 800 años, en el sentido de que todas las 48 categorías se identifican en todas las épocas del corpus. El uso de "de" como complemento nominal va aumentando, al contrario de lo que ocurre con su uso como complemento verbal. En el contexto nominal son especialmente las relaciones posesivas más abstractas las que se hacen más frecuentes, mientras que en el contexto verbal las relaciones que se hacen menos frecuentes son las de separación/alejamiento, causa, agente y partitivo indefinido. Destaca la importancia del siglo XVIII como época de transición entre un primer estado de las cosas y otro posterior, en especial en relación con el carácter cada vez más abstracto de las relaciones posesivas así como con la disminución de las categorías adverbales de causa, agente y partitivo. Pese a la variación en el contexto inmediato de uso, el núcleo semántico de "de" se mantiene inalterado. La parte III toma como punto de partida los resultados del análisis de la parte II, tratando de deslindar el aporte semántico de la preposición "de" a su contexto de uso del valor de la relación en conjunto. Así, recurriendo a la metodología para determinar el significado básico y la metodología para determinar lo que constituyen significados distintos de una preposición (Tyler , Evans 2003a, 2003b), se llega a la hipótesis de que "de" posee cuatro significados básicos, a saber, 'punto de partida', 'tema/asunto', 'parte/todo' y 'posesión'. Esta hipótesis, basada en las metodologías de Tyler y Evans y en los resultados del análisis de corpus, se intenta verificar empíricamente mediante el uso de dos cuestionarios destinados a averiguar hasta qué punto las distinciones semánticas a las que se llega por vía teórica son reconocidas por los hablantes nativos de la lengua (cf. Raukko 2003). El resultado conjunto de los dos acercamientos tanto refuerza como especifica la hipótesis. Los datos que arroja el análisis de los cuestionarios parecen reforzar la idea de que el núcleo semántico de "de" es complejo, constando de los cuatro valores mencionados. Sin embargo, cada uno de estos valores básicos constituye un prototipo local, en torno al cual se construye un complejo de matices semánticos derivados del prototipo. La idea final es que los hablantes son conscientes de los cuatro postulados valores básicos, pero que también distinguen matices más detallados, como son las ideas de 'causa', 'agente', 'instrumento', 'finalidad', 'cualidad', etc. Es decir, "de" constituye un elemento polisémico complejo cuya estructura semántica puede describirse como una semejanza de familia centrada en cuatro valores básicos en torno a los cuales se encuentra una serie de matices más específicos, que también constituyen valores propios de la preposición. Creemos, además, que esta caracterización semántica es válida para todas las épocas de la historia del español, con unas pequeñas modificaciones en el peso relativo de los distintos matices, lo cual está relacionado con la observada variación diacrónica en el uso de "de".