Agreement Patterns in English : Diachronic Corpus Studies on Common-Number Pronouns

This study reports a diachronic corpus investigation of common-number pronouns used to convey unknown or otherwise unspecified reference. The study charts agreement patterns in these pronouns in various diachronic and synchronic corpora. The objective is to provide base-line data on variant frequencies and distributions in the history of English, as there are no previous systematic corpus-based observations on this topic. This study seeks to answer the questions of how pronoun use is linked with the overall typological development in English and how their diachronic evolution is embedded in the linguistic and social structures in which they are used. The theoretical framework draws on corpus linguistics and historical sociolinguistics, grammaticalisation, diachronic typology, and multivariate analysis of modelling sociolinguistic variation. The method employs quantitative corpus analyses from two main electronic corpora, one from Modern English and the other from Present-day English. The Modern English material is the Corpus of Early English Correspondence, and the time frame covered is 1500-1800. The written component of the British National Corpus is used in the Present-day English investigations. In addition, the study draws supplementary data from other electronic corpora. The material is used to compare the frequencies and distributions of common-number pronouns between these two time periods. The study limits the common-number uses to two subsystems, one anaphoric to grammatically singular antecedents and one cataphoric, in which the pronoun is followed by a relative clause. Various statistical tools are used to process the data, ranging from cross-tabulations to multivariate VARBRUL analyses in which the effects of sociolinguistic and systemic parameters are assessed to model their impact on the dependent variable. This study shows how one pronoun type has extended its uses in both subsystems, an increase linked with grammaticalisation and the changes in other pronouns in English through the centuries. The variationist sociolinguistic analysis charts how grammaticalisation in the subsystems is embedded in the linguistic and social structures in which the pronouns are used. The study suggests a scale of two statistical generalisations of various sociolinguistic factors which contribute to grammaticalisation and its embedding at various stages of the process.

Mitochondrial helicase Twinkle in mtDNA copy number regulation and a late-onset disease model

Mitochondrial diseases are caused by disturbances of the energy metabolism. The disorders range from severe childhood neurological diseases to muscle diseases of adults. Recently, mitochondrial dysfunction has also been found in Parkinson s disease, diabetes, certain types of cancer and premature aging. Mitochondria are the power plants of the cell but they also participate in the regulation of cell growth, signaling and cell death. Mitochondria have their own genetic material, mtDNA, which contains the genetic instructions for cellular respiration. Single cell may host thousands of mitochondria and several mtDNA molecules may reside inside single mitochondrion. All proteins needed for mtDNA maintenance are, however, encoded by the nuclear genome, and therefore, mutations of the corresponding genes can also cause mitochondrial disease. We have here studied the function of mitochondrial helicase Twinkle. Our research group has previously identified nuclear Twinkle gene mutations underlying an inherited adult-onset disorder, progressive external ophthalmoplegia (PEO). Characteristic for the PEO disease is the accumulation of multiple mtDNA deletions in tissues such as the muscle and brain. In this study, we have shown that Twinkle helicase is essential for mtDNA maintenance and that it is capable of regulating mtDNA copy number. Our results support the role of Twinkle as the mtDNA replication helicase. No cure is available for mitochondrial disease. Good disease models are needed for studies of the cause of disease and its progression and for treatment trials. Such disease model, which replicates the key features of the PEO disease, has been generated in this study. The model allows for careful inspection of how Twinkle mutations lead to mtDNA deletions and further causes the PEO disease. This model will be utilized in a range of studies addressing the delay of the disease onset and progression and in subsequent treatment trials. In conclusion, in this thesis fundamental knowledge of the function of the mitochondrial helicase Twinkle was gained. In addition, the first model for adult-onset mitochondrial disease was generated.

Aerosol size distribution and its connection to cloud droplet number concentration

In order to predict the current state and future development of Earth s climate, detailed information on atmospheric aerosols and aerosol-cloud-interactions is required. Furthermore, these interactions need to be expressed in such a way that they can be represented in large-scale climate models. The largest uncertainties in the estimate of radiative forcing on the present day climate are related to the direct and indirect effects of aerosol. In this work aerosol properties were studied at Pallas and Utö in Finland, and at Mount Waliguan in Western China. Approximately two years of data from each site were analyzed. In addition to this, data from two intensive measurement campaigns at Pallas were used. The measurements at Mount Waliguan were the first long term aerosol particle number concentration and size distribution measurements conducted in this region. They revealed that the number concentration of aerosol particles at Mount Waliguan were much higher than those measured at similar altitudes in other parts of the world. The particles were concentrated in the Aitken size range indicating that they were produced within a couple of days prior to reaching the site, rather than being transported over thousands of kilometers. Aerosol partitioning between cloud droplets and cloud interstitial particles was studied at Pallas during the two measurement campaigns, First Pallas Cloud Experiment (First PaCE) and Second Pallas Cloud Experiment (Second PaCE). The method of using two differential mobility particle sizers (DMPS) to calculate the number concentration of activated particles was found to agree well with direct measurements of cloud droplet. Several parameters important in cloud droplet activation were found to depend strongly on the air mass history. The effects of these parameters partially cancelled out each other. Aerosol number-to-volume concentration ratio was studied at all three sites using data sets with long time-series. The ratio was found to vary more than in earlier studies, but less than either aerosol particle number concentration or volume concentration alone. Both air mass dependency and seasonal pattern were found at Pallas and Utö, but only seasonal pattern at Mount Waliguan. The number-to-volume concentration ratio was found to follow the seasonal temperature pattern well at all three sites. A new parameterization for partitioning between cloud droplets and cloud interstitial particles was developed. The parameterization uses aerosol particle number-to-volume concentration ratio and aerosol particle volume concentration as the only information on the aerosol number and size distribution. The new parameterization is computationally more efficient than the more detailed parameterizations currently in use, but the accuracy of the new parameterization was slightly lower. The new parameterization was also compared to directly observed cloud droplet number concentration data, and a good agreement was found.

Patient doses in ct, dental cone beam ct and projection radiography in Finland, with emphasis on paediatric patients

Diagnostic radiology represents the largest man-made contribution to population radiation doses in Europe. To be able to keep the diagnostic benefit versus radiation risk ratio as high as possible, it is important to understand the quantitative relationship between the patient radiation dose and the various factors which affect the dose, such as the scan parameters, scan mode, and patient size. Paediatric patients have a higher probability for late radiation effects, since longer life expectancy is combined with the higher radiation sensitivity of the developing organs. The experience with particular paediatric examinations may be very limited and paediatric acquisition protocols may not be optimised. The purpose of this thesis was to enhance and compare different dosimetric protocols, to promote the establishment of the paediatric diagnostic reference levels (DRLs), and to provide new data on patient doses for optimisation purposes in computed tomography (with new applications for dental imaging) and in paediatric radiography. Large variations in radiation exposure in paediatric skull, sinus, chest, pelvic and abdominal radiography examinations were discovered in patient dose surveys. There were variations between different hospitals and examination rooms, between different sized patients, and between imaging techniques; emphasising the need for harmonisation of the examination protocols. For computed tomography, a correction coefficient, which takes individual patient size into account in patient dosimetry, was created. The presented patient size correction method can be used for both adult and paediatric purposes. Dental cone beam CT scanners provided adequate image quality for dentomaxillofacial examinations while delivering considerably smaller effective doses to patient compared to the multi slice CT. However, large dose differences between cone beam CT scanners were not explained by differences in image quality, which indicated the lack of optimisation. For paediatric radiography, a graphical method was created for setting the diagnostic reference levels in chest examinations, and the DRLs were given as a function of patient projection thickness. Paediatric DRLs were also given for sinus radiography. The detailed information about the patient data, exposure parameters and procedures provided tools for reducing the patient doses in paediatric radiography. The mean tissue doses presented for paediatric radiography enabled future risk assessments to be done. The calculated effective doses can be used for comparing different diagnostic procedures, as well as for comparing the use of similar technologies and procedures in different hospitals and countries.

The EU and Institutional Twinning in Morocco - An inquiry into the motives of cooperation through discourse ethics

This study examines Institutional Twinning in Morocco as a case of EU cooperation through the pragmatic, ethical and moral logics of reason in Jürgen Habermas’s discourse ethics. As a former accession tool, Twinning was introduced in 2004 for legal approximation in the context of the European Neighborhood Policy. Twinning is a unique instrument in development cooperation from a legal perspective. With its long historical and cultural ties to Europe, Morocco presents an interesting case study of this new form of cooperation. We will analyse motives behind the Twinning projects on illegal immigration, environment legislation and customs reform. As Twinning is a new policy instrument within the ENP context, there is relatively little preceding research, which, in itself, constitutes a reason to inquire into the subject. While introducing useful categories, the approaches discussing “normative power Europe” do not offer methodological tools precise enough to analyse the motives of the Twinning cooperation from a broad ethical standpoint. Helene Sjursen as well as Esther Barbé and Elisabeth Johansson-Nogués have elaborated on Jürgen Habermas’ discourse ethics in determining the extent of altruism in the ENP in general. Situating the analysis in the process-oriented framework of Critical Theory, discourse ethics provides the methodological framework for our research. The case studies reveal that the context in which they operate affects the pragmatic, ethical and moral aspirations of the actors. The utilitarian notion of profit maximization is quite pronounced both in terms of the number of Twinning projects in the economic sphere and the pragmatic logics of reason instrumental to security and trade-related issues. The historical background as well internal processes, however, contribute to defining areas of mutual interest to the actors as well as the motives Morocco and the EU sometimes described as the external projection of internal values. Through its different aspects, Twinning cooperation portrays the functioning of the pragmatic, ethical and moral logics of reason in international relations.

MECHANISMS AND EFFECTS OF MITOCHONDRIAL DNA INSTABILITY AND COPY NUMBER MANIPULATION

Defects in mitochondrial DNA (mtDNA) maintenance cause a range of human diseases, including autosomal dominant progressive external ophthalmoplegia (adPEO). This study aimed to clarify the molecular background of adPEO. We discovered that deoxynucleoside triphosphate (dNTP) metabolism plays a crucial in mtDNA maintenance and were thus prompted to search for therapeutic strategies based on the modulation of cellular dNTP pools or mtDNA copy number. Human mtDNA is a 16.6 kb circular molecule present in hundreds to thousands of copies per cell. mtDNA is compacted into nucleoprotein clusters called nucleoids. mtDNA maintenance diseases result from defects in nuclear encoded proteins that maintain the mtDNA. These syndromes typically afflict highly differentiated, post-mitotic tissues such as muscle and nerve, but virtually any organ can be affected. adPEO is a disease where mtDNA molecules with large-scale deletions accumulate in patients tissues, particularly in skeletal muscle. Mutations in five nuclear genes, encoding the proteins ANT1, Twinkle, POLG, POLG2 and OPA1, have previously been shown to cause adPEO. Here, we studied a large North American pedigree with adPEO, and identified a novel heterozygous mutation in the gene RRM2B, which encodes the p53R2 subunit of the enzyme ribonucleotide reductase (RNR). RNR is the rate-limiting enzyme in dNTP biosynthesis, and is required both for nuclear and mitochondrial DNA replication. The mutation results in the expression of a truncated form of p53R2, which is likely to compete with the wild-type allele. A change in enzyme function leads to defective mtDNA replication due to altered dNTP pools. Therefore, RRM2B is a novel adPEO disease gene. The importance of adequate dNTP pools and RNR function for mtDNA maintenance has been established in many organisms. In yeast, induction of RNR has previously been shown to increase mtDNA copy number, and to rescue the phenotype caused by mutations in the yeast mtDNA polymerase. To further study the role of RNR in mammalian mtDNA maintenance, we used mice that broadly overexpress the RNR subunits Rrm1, Rrm2 or p53R2. Active RNR is a heterotetramer consisting of two large subunits (Rrm1) and two small subunits (either Rrm2 or p53R2). We also created bitransgenic mice that overexpress Rrm1 together with either Rrm2 or p53R2. In contrast to the previous findings in yeast, bitransgenic RNR overexpression led to mtDNA depletion in mouse skeletal muscle, without mtDNA deletions or point mutations. The mtDNA depletion was associated with imbalanced dNTP pools. Furthermore, the mRNA expression levels of Rrm1 and p53R2 were found to correlate with mtDNA copy number in two independent mouse models, suggesting nuclear-mitochondrial cross talk with regard to mtDNA copy number. We conclude that tight regulation of RNR is needed to prevent harmful alterations in the dNTP pool balance, which can lead to disordered mtDNA maintenance. Increasing the copy number of wild-type mtDNA has been suggested as a strategy for treating PEO and other mitochondrial diseases. Only two proteins are known to cause a robust increase in mtDNA copy number when overexpressed in mice; the mitochondrial transcription factor A (TFAM), and the mitochondrial replicative helicase Twinkle. We studied the mechanisms by which Twinkle and TFAM elevate mtDNA levels, and showed that Twinkle specifically implements mtDNA synthesis. Furthermore, both Twinkle and TFAM were found to increase mtDNA content per nucleoid. Increased mtDNA content in mouse tissues correlated with an age-related accumulation of mtDNA deletions, depletion of mitochondrial transcripts, and progressive respiratory dysfunction. Simultaneous overexpression of Twinkle and TFAM led to a further increase in the mtDNA content of nucleoids, and aggravated the respiratory deficiency. These results suggested that high mtDNA levels have detrimental long-term effects in mice. These data have to be considered when developing and evaluating treatment strategies for elevating mtDNA copy number.

Population projection for Namibia 2011-2020 - With an estimation of the impact of HIV/AIDS

This study presents a population projection for Namibia for years 2011–2020. In many countries of sub-Saharan Africa, including Namibia, the population growth is still continuing even though the fertility rates have declined. However, many of these countries suffer from a large HIV epidemic that is slowing down the population growth. In Namibia, the epidemic has been severe. Therefore, it is important to assess the effect of HIV/AIDS on the population of Namibia in the future. Demographic research on Namibia has not been very extensive, and data on population is not widely available. According to the studies made, fertility has been shown to be generally declining and mortality has been significantly increasing due to AIDS. Previous population projections predict population growth for Namibia in the near future, yet HIV/AIDS is affecting the future population developments. For the projection constructed in this study, data on population is taken from the two most recent censuses, from 1991 and 2001. Data on HIV is available from HIV Sentinel Surveys 1992–2008, which test pregnant women for HIV in antenatal clinics. Additional data are collected from different sources and recent studies. The projection is made with software (EPP and Spectrum) specially designed for developing countries with scarce data. The projection includes two main scenarios which have different assumptions concerning the development of the HIV epidemic. In addition, two hypothetical scenarios are made: the first considering the case where HIV epidemic would never have existed and the second considering the case where HIV treatment would never have existed. The results indicate population growth for Namibia. Population in the 2001 census was 1.83 million and is projected to result in 2.38/2.39 million in 2020 in the first two scenarios. Without HIV, population would be 2.61 million and without treatment 2.30 million in 2020. Urban population is growing faster than rural. Even though AIDS is increasing mortality, the past high fertility rates still keep young adult age groups quite large. The HIV epidemic shows to be slowing down, but it is still increasing the mortality of the working-aged population. The initiation of HIV treatment in 2004 in the public sector seems to have had an effect on many projected indicators, diminishing the impact of HIV on the population. For example, the rise of mortality is slowing down.

Integration of miRNA and mRNA expression with DNA copy number of Ewing sarcoma cell lines

Ewing sarcoma is an aggressive and poorly differentiated malignancy of bone and soft tissue. It primarily affects children, adolescents, and young adults, with a slight male predominance. It is characterized by a translocation between chromosomes 11 and 22 resulting in the EWSR1-FLI1fusion transcription factor. The aim of this study is to identify putative Ewing sarcoma target genes through an integrative analysis of three microarray data sets. Array comparative genomic hybridization is used to measure changes in DNA copy number, and analyzed to detect common chromosomal aberrations. mRNA and miRNA microarrays are used to measure expression of protein-coding and miRNA genes, and these results integrated with the copy number data. Chromosomal aberrations typically contain also bystanders in addition to the driving tumor suppressor and oncogenes, and integration with expression helps to identify the true targets. Correlation between expression of miRNAs and their predicted target mRNAs is also evaluated to assess the results of post-transcriptional miRNA regulation on mRNA levels. The highest frequencies of copy number gains were identified in chromosome 8, 1q, and X. Losses were most frequent in 9p21.3, which also showed an enrichment of copy number breakpoints relative to the rest of the genome. Copy number losses in 9p21.3 were found have a statistically significant effect on the expression of MTAP, but not on CDKN2A, which is a known tumor-suppressor in the same locus. MTAP was also down-regulated in the Ewing sarcoma cell lines compared to mesenchymal stem cells. Genes exhibiting elevated expression in association with copy number gains and up-regulation compared to the reference samples included DCAF7, ENO2, MTCP1, andSTK40. Differentially expressed miRNAs were detected by comparing Ewing sarcoma cell lines against mesenchymal stem cells. 21 up-regulated and 32 down-regulated miRNAs were identified, includingmiR-145, which has been previously linked to Ewing sarcoma. The EWSR1-FLI1 fusion gene represses miR-145, which in turn targets FLI1 forming a mutually repressive feedback loop. In addition higher expression linked to copy number gains and compared to mesenchymal stem cells, STK40 was also found to be a target of four different miRNAs that were all down-regulated in Ewing sarcoma cell lines compared to the reference samples. SLCO5A1 was identified as the only up-regulated gene within a frequently gained region in chromosome 8. This region was gained in over 90 % of the cell lines, and also with a higher frequency than the neighboring regions. In addition, SLCO5A1 was found to be a target of three miRNAs that were down-regulated compared to the mesenchymal stem cells.

The EU and Institutional Twinning in Morocco - An inquiry into the motives of cooperation through discourse ethics

This study examines Institutional Twinning in Morocco as a case of EU cooperation through the pragmatic, ethical and moral logics of reason in Jürgen Habermas’s discourse ethics. As a former accession tool, Twinning was introduced in 2004 for legal approximation in the context of the European Neighborhood Policy. Twinning is a unique instrument in development cooperation from a legal perspective. With its long historical and cultural ties to Europe, Morocco presents an interesting case study of this new form of cooperation. We will analyse motives behind the Twinning projects on illegal immigration, environment legislation and customs reform. As Twinning is a new policy instrument within the ENP context, there is relatively little preceding research, which, in itself, constitutes a reason to inquire into the subject. While introducing useful categories, the approaches discussing “normative power Europe” do not offer methodological tools precise enough to analyse the motives of the Twinning cooperation from a broad ethical standpoint. Helene Sjursen as well as Esther Barbé and Elisabeth Johansson-Nogués have elaborated on Jürgen Habermas’ discourse ethics in determining the extent of altruism in the ENP in general. Situating the analysis in the process-oriented framework of Critical Theory, discourse ethics provides the methodological framework for our research. The case studies reveal that the context in which they operate affects the pragmatic, ethical and moral aspirations of the actors. The utilitarian notion of profit maximization is quite pronounced both in terms of the number of Twinning projects in the economic sphere and the pragmatic logics of reason instrumental to security and trade-related issues. The historical background as well internal processes, however, contribute to defining areas of mutual interest to the actors as well as the motives Morocco and the EU sometimes described as the external projection of internal values. Through its different aspects, Twinning cooperation portrays the functioning of the pragmatic, ethical and moral logics of reason in international relations.