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.

Afrikkalaisen sikaruton mahdollisia maahantuloreittejä

Afrikkalainen sikarutto on lakisääteisesti vastustettava helposti leviävä sikojen ja villisikojen virustauti, jolla on myös vakavia sosioekonomisia vaikutuksia. Akuutissa tautimuodossa eläimillä esiintyy syömättömyyttä, korkeaa kuumetta, verenpurkaumia iholla, veristä ulostetta sekä mahdollisesti ripulia. Kuolleisuus on lähes 100 % ja tauti johtaa kuolemaan 7-10 vrk tartunnan jälkeen. Tauti ei tartu ihmisiin. Tautia esiintyy sekä kesy- että villisioissa suurimmassa osassa Saharan eteläpuolista Afrikkaa ja Sardiniassa. Vuodesta 2007 lähtien tautia on esiintynyt Kaukasuksen alueella ja vuonna 2011 lähellä Suomen rajaa: Leningradin alueella ja Kuolan niemimaalla. Tässä riskiprofiilissa kartoitetaan reitit ja tapahtumasarjat, jotka voivat johtaa siihen, että afrikkalainen sikarutto tulee Suomeen ensimmäisen kerran. Näistä oleellisimmat ovat: maahantulo infektioalueella matkustaneiden ihmisten mukana, infektoituneen lihan tai lihatuotteen mukana, elävien kesysikojen ja sperman mukana, kontaminoituneiden eläinkuljetusajoneuvojen mukana, kansainvälisen liikenteen ruokajätteen mukana ja Suomeen vaeltavan infektoituneen villisian mukana. Tilatason tautisuojaus sekä tehokas ja kohdennettu tiedottaminen taudin vaaroista ovat avainasemassa, kun halutaan suojata Suomen sikaelinkeinoa afrikkalaiselta sikarutolta.

Proofs, Paradoxes, and Probabilities : The Logical Turn of Philosophy in Finland

This monograph describes the emergence of independent research on logic in Finland. The emphasis is placed on three well-known students of Eino Kaila: Georg Henrik von Wright (1916-2003), Erik Stenius (1911-1990), and Oiva Ketonen (1913-2000), and their research between the early 1930s and the early 1950s. The early academic work of these scholars laid the foundations for today's strong tradition in logic in Finland and also became internationally recognized. However, due attention has not been given to these works later, nor have they been comprehensively presented together. Each chapter of the book focuses on the life and work of one of Kaila's aforementioned students, with a fourth chapter discussing works on logic by authors who would later become known within other disciplines. Through an extensive use of correspondence and other archived material, some insight has been gained into the persons behind the academic personae. Unique and unpublished biographical material has been available for this task. The chapter on Oiva Ketonen focuses primarily on his work on what is today known as proof theory, especially on his proof theoretical system with invertible rules that permits a terminating root-first proof search. The independency of the parallel postulate is proved as an example of the strength of root-first proof search. Ketonen was to our knowledge Gerhard Gentzen's (the 'father' of proof theory) only student. Correspondence and a hitherto unavailable autobiographic manuscript, in addition to an unpublished article on the relationship between logic and epistemology, is presented. The chapter on Erik Stenius discusses his work on paradoxes and set theory, more specifically on how a rigid theory of definitions is employed to avoid these paradoxes. A presentation by Paul Bernays on Stenius' attempt at a proof of the consistency of arithmetic is reconstructed based on Bernays' lecture notes. Stenius correspondence with Paul Bernays, Evert Beth, and Georg Kreisel is discussed. The chapter on Georg Henrik von Wright presents his early work on probability and epistemology, along with his later work on modal logic that made him internationally famous. Correspondence from various archives (especially with Kaila and Charlie Dunbar Broad) further discusses his academic achievements and his experiences during the challenging circumstances of the 1940s.

Finlandssvenska åsikter om och attityder till modern språkpåverkan

The study describes and analyzes Finland Swedes attitudes to modern-day linguistic influence, the relationship between informants explicitly reported views and the implicit attitudes they express towards language influence. The methods are primarily sociolinguistic. For the analysis of opinions and attitudes I have further developed and tested a new tool in attitude research. With statistical correlation analysis of data collected through a quantitative survey I describe the views that Swedish-language Finns (N=500) report on the influence of English, on imports, and on domain loss. With experimental matchedguise techniques, I study Finland-Swedes (N=600) subconscious reactions to English imports in spoken text. My results show that the subconscious reactions in some respects differ markedly from the views informants explicitly report that they have: informants respond that they would like English words that come into Swedish to be replaced by Swedish replacement words, but in a matched-guise test on their subconscious attitudes, the informants consider English words in a Swedish context to have a positive effect. The topic is further dealt with in interviews where I examine 36 informants implicit attitudes through interactional sociolinguistic analyses. This study comes close to pragmatic discourse analysis in its focus on pragmatic particles and modality. The study makes a rather strict distinction between explicitly expressed opinions and implicit, subconscious attitudes. The quantitative analyses suggest that the opinions we express can be tied to the explicit in language. The outcome of the matched-guise test shows that it is furthermore possible to find subconscious, implicit attitudes that people in actual situations rely on when they make decisions. The discourse analysis finds many subconscious signals, but it also shows that the signals arise in interaction with one s interlocutor, the situation, and the norms in the society. To account for this I have introduced the concept of socioconscious attitude. Socioconscious attitudes reflect not only the traditions and values the utterer grew up with, but also the speaker s relation to the social situation (s)he takes part in.

Deutschland, Deutschland über alles : Tysk föreningsverksamhet i Finland och Sverige 1910-1950

The voluntary associations dealt with in this dissertation were ethnic clubs and societies promoting the interests of German immigrants in Finland and Sweden. The associations were founded at the end of the 19th century as well as at the beginning of the 20th century during a time in which migration was high, the civil society grew rapidly and nationalism flourished. The work includes over 70 different associations in Finland and Sweden with a number of members ranging from ten to at most 2, 500. The largest and most important associations were situated in Helsinki and Stockholm where also most of the German immigrants lived. The main aim of this work is to explore to what extent and how the changes in government in Germany during 1910 to 1950 were reflected in the structures and participants, financial resources and meeting places, networks and activities of the German associations in Finland and Sweden. The study also deals with how a collective German national identity was created within the German associations. The period between 1910 and 1950 has been described by Hobsbawm as the apogee of nationalism. Nationalism and transnationalism are therefore key elements in the work. Additionally the research deals with theories about associations, networking and identity. The analysis is mostly based on minutes of meetings, descriptions of festivities, annual reports and historical outlines about the associations. Archival sources from the German legations, the German Foreign Office, and Finnish and Swedish officials such as the police and the Foreign Offices are also used. The study shows that the collective national identity in the associations during the Weimar Republic mostly went back to the time of the Wilhelmine Empire. It is argued that this fact, the cultural propaganda and the aims of the Weimar Republic to strengthen the contacts between Germany and the German associations abroad, and the role of the German legations and envoys finally helped the small groups of NSDAP to infiltrate, systematically coordinate and finally centralize the German associational life in Finland and Sweden. The Gleichschaltung did not go as smoothly as the party wanted, though. There was a small but consistent opposition that continued to exist in Finland until 1941 and in Sweden until 1945. The collective national identity was displayed much more in Sweden than in Finland, where the associations kept a lower profile. The reasons for the profile differences can be found in the smaller number of German immigrants in Finland and the greater German propaganda in Sweden, but also in the Finnish association act from 1919 and the changes in it during the 1920s and 1930s. Finally, the research shows how the loss of two world wars influenced the associations. It argues that 1918 made the German associations more vulnerable to influence from Germany, whereas 1945 brought the associational life back to where it once started as welfare, recreational and school associations.

Design of NRAs having higher aperture opening ratio and autocorrelation compression ratio by means of a global optimization method

When noises considerations are made, nonredundant arrays (NRAs) are endowed with many advantages which other arrays e.g., uniformly redundant arrays (URAs) do not possess in applications of coded aperture imaging. However, lower aperture opening ratio limits the applications of NRA in practice. In this paper, we present a computer searching method based on a global optimization algorithm named DIRECT to design NRAs. Compared with the existing NRAs e.g., Golay's NRAs, which are well known and widely used in various applications, NRAs found by our method have higher aperture opening ratio and auto correlation compression ratio. These advantages make our aperture arrays be very useful for practical applications especially for which of aperture size are limited. Here, we also present some aperture arrays we found. These aperture arrays have an interesting property that they belong to both NRA and URA. (C) 2006 Elsevier GmbH. All rights reserved.

The River Lune strategic stock assessment survey 1991 with particular reference to salmonids

In the past stock assessment surveys were generally reactive in response to a particular problem e.g. a pollution incident and as such were limited in the information they provided. A programme of strategic stock assessment would be more beneficial, providing up to date information on the status and composition of the stock. On a national level this could reveal trends in population dynamics and enable comparisons to be made between key rivers and between regions. The Stock Assessment Task Group (1991) has recommended annual strategic surveys for juvenile salmonids and triennial strategic surveys for coarse fish and non- migratory salmonids. The aim of this pilot study was to gain information on species distribution and their relative abundance within the River Lune catchment, and to compare the findings with the surveys carried out between 1981-1985. This would provide valuable information on the current status of the stock and provide an indication of the resources required to conduct such strategic surveys on other river catchments in the North West Region of the National Rivers Authority.

The juvenile salmonid populations of the River Lune catchment, 1981 to 1985

The aim of this study was to assess the status of the juvenile salmonid populations of the River Lune and its tributaries. There was special emphasis on juvenile salmon stocks in view of the implementation of a net limitation order in 1980. The number of licensed instruments were reduced as follows: (1) Drift, hang or whammel nets - from 12 to 10 (2) Draft or seine nets - from 3 to 1 (3) Heave or haaf nets - from 4 6 to 2 6 For the purpose of this report, the River Lune system has been divided into 13 subcatchments and these are examined with a view to detecting any trends in the data such as subcatchment productivity, partitioning between salmon and trout nursery streams, and whether the restrictions on salmon fishing had any discernible effects on juvenile salmon productivity. The effect of flow and instream obstructions on salmonid densities are also investigated as these have been shown to be important factors affecting abundance. Throughout the study period a programme of enhancement stocking took place primarily with salmon ova and fry. The possible impact of this on the results of the surveys has been assessed. The distribution and abundance of juvenile salmon was found to be relatively consistent in each of the 13 subcatchments studied over the 1981-1985 period.

A summary report on juvenile salmonid populations of the River Lune catchment, 1981 to 1991

This report summarises the fisheries electrofishing survey work undertaken on the River Lune, England, in the period 1981-85 and 1991. As part of a long term monitoring programme by the National Rivers Authority, juvenile surveys, with the emphasis on salmonids, have been carried out on the River Lune on a number of occasions since 1981. The latest survey in 1991 now gives the opportunity to assess what, if any, changes have occurred in the juvenile populations across the last 11 years and how future fisheries management may impact on the River Lune as a fishery. The areas of trout and salmon, fry and parr production will be considered in detail, as will adult trout populations. Water quality issues will be mentioned briefly as will habitat issues, where they are deemed to be important in affecting fish densities.

A report on the population structure of adult salmon and sea trout in the River Lune using scale samples - with reference to historical data.

During 1993, a comprehensive data set of scale readings, length and weight measurements was established for migratory salmonids on the River Lune. This information was collected using three methods of fish capture: 1. The Lune estuary commercial nets. 2. River Lune Forge weir fish trap. 3. River Lune rod catch scale returns. Additional information was contributed by the Kent, Leven and Duddon rod and commercial fisheries. The data shows that the salmon stock in 1993 was dominated by two year old smolts. This varies from year to year. The sea trout population displays a normal population curve in terms of numbers of fish in each age and weight class. The growth rate of salmon and sea trout is very similar even though salmon have the benefit of high sea feeding.

Report on the collection of salmon creel census data from Rivers Ribble and Hodder

The River Ribble bailiff team completed a total of 377 salmonid creel censuses by interviewing anglers fishing on the banks of the Rivers Ribble and Hodder during 1994. The study was undertaken for a number of reasons: (i) , To determine which areas of the river were fished by anglers. (ii) To ascertain which fishing methods were used in these areas. (iii) To identify the success of each fishing method within each area of the River Ribble system. In a limited 1993 sampling programme, 55 censuses were carried out. Results from these indicated that fishing with worm as bait was the most common method (39% of anglers interviewed) and also resulted in the greatest number of salmon being caught (61% of all salmon). The 1994 census data were collected from all areas of the Ribble system during the months of June to October. The data presented here are for anglers fishing for salmon only or for those fishing for salmon and sea trout at the same time. All of the fish caught were salmon.

An analysis of the historical catch data from the migratory salmonid fisheries of the River Ribble

The Ribble catchment is the largest and most diverse river system within National Rivers Authority (NRA), North West's Central Area. The river is approximately 100km in length and rises in a limestone area west of the Pennines. This report examines changes in the size and composition of the salmon and sea trout catches from the Ribble migratory salmonid fisheries during the years 1937 to 1991. Comparisons are made between the rod and net fisheries for both salmon and sea trout of the Ribble and Hodder. Patterns of catches shown by the Ribble fisheries are compared with those of other individual rivers and with patterns for the North West Region as a whole. An attempt is made to identify if any relationship exists between catch and stock abundance. Catch patterns shown by the Ribble and Hodder salmon fisheries are compared with electronic resistivity counter data from the two rivers. Annual salmon catch patterns and redd count data are compared both locally and regionally. Recommendations for future studies are made in the light of the report's findings.

Report on the analysis of salmon scale samples returned by anglers on the Rivers Ribble and Hodder

Fisheries technical staff from the North West Central Area of the National Rivers Authority (NRA) currently provide a service for the ageing of salmon scales from fish caught by anglers on the Rivers Ribble and Hodder in order to gather information on the biological characteristics of the salmon population on the River Ribble system in terms of weight, freshwater age and sea age. At the beginning of each fishing season, scale envelopes are distributed by the NRA to angling clubs and some individual anglers. Scales taken from salmon caught on the rivers are returned to the NRA Central Area Office by the anglers, or more often, by NRA bailiffs. The age of each fish caught is then determined by the identification and counting of annuli for both the river and sea zones on the scale. Information is provided by the angler on the scale packet concerning the length and weight of the fish caught, and the date, location and method of capture. Both this information and the age of the fish is recorded on a database. These data can be used to investigate the distribution, and exploitation patterns of the different age classes of the salmon stock within the river system. This report is principally concerned with the scale samples received in 1994, although comparison is also made with samples from 1993 and 1992. References to data will all relate to that received in 1994 unless an alternate year is stated.

Report on the 1992 stock assessment of the Wyre catchment

The aim of this study was to assess the status of the juvenile salmonid and coarse fish populations of the Wyre catchment. Emphasis was placed on an examination of the distribution of spawning and nursery areas for salmonids within the study area and an assessment of the status of juvenile salmonid stocks. The species distribution and spawning areas for other fish species were also identified where possible and the status of the Wyre coarse fishery, downstream of Churchtown Weir, assessed. This report examines the results of stock assessment surveys carried out in the Wyre catchment between 2/06/92 and 11/08/92. Forty-six sites were surveyed from Tarnbrook Wyre (SD. 598577) and Marshaw Wyre (SD. 614541) downstream to St Michaels (SD. 465411). Flow, habitat and in-river obstructions have been shown to affect juvenile salmonid densities. A habitat description is provided for each site studied during the course of this study.

Report on the 1994 juvenile salmon stocking study of Foxhouses and Grizedale Becks, River Wyre

The aim of this study was to assess the suitability of Foxhouses and Grizedale Becks as nursery habitat for juvenile salmon. A comprehensive fish stock assessment survey of the Wyre catchment was carried out by the NRA in 1992. This survey found that juvenile salmon were absent from two sites studied in Foxhouses Beck. In one site in Grizedale Beck, 0+ salmon were found at very low densities. Juvenile trout were found in all three sites studied in 1992. On the basis of the results of the 1992 survey, these two becks were stocked in 1994 with 0+ salmon reared from Lune broodstock at the NRA's Witcherwell Hatchery. These salmon were stocked at a known density, following a pre-stocking survey. This report examines and compares the results of the pre-stocking survey consisting of fourteen sites in the two becks, carried out between 12/04/94 and 27/04/94 and a post- stocking survey of six sites, carried out between 12/10/94 and 19/10/94. Flow, habitat and in-river obstructions have been shown to affect juvenile salmonid densities. A habitat description is provided for each site surveyed during the course of this study.