Animal model and molecular interactions of Cln5

Neuronal ceroid lipofuscinoses (NCLs) are a family of inherited pediatric neurodegenerative disorders, leading to retinal degeneration, death of selective neuronal populations and accumulation of autofluorscent ceroid-lipopigments. The clinical manifestations are generally similar in all forms. The Finnish variant late infantile neuronal ceroid lipofuscinosis (vLINCLFin) is a form of NCL, especially enriched in the Finnish population. The aim of this thesis was to analyse the brain pathology of vLINCLFin utilising the novel Cln5-/- mouse model. Gene expression profiling of the brains of already symptomatic Cln5-/- mice revealed that inflammation, neurodegeneration and defects in myelinization are the major characteristics of the later stages of the disease. Histological characterization of the brain pathology confirmed that the thalamocortical system is affected in Cln5-/- mice, similarly to the other NCL mouse models. However, whereas the brain pathology in all other analyzed NCL mice initiate in the thalamus and spread only months later to the cortex, we observed that the sequence of events is uniquely reversed in Cln5-/- mice; beginning in the cortex and spreading to the thalamus only months later. We could also show that even though neurodegeneration is inititated in the cortex, reactive gliosis and loss of myelin are evident in specific nuclei of the thalamus already in the 1 month old brain. To obtain a deeper insight into the disturbed metabolic pathways, we performed gene expression profiling of presymptomatic mouse brains. We validated these findings with immunohistological analyses, and could show that cytoskeleton and myelin were affected in Cln5-/- mice. Comparison of gene expression profiling results of Cln5-/- and Cln1-/- mice, further highlighted that these two NCL models share a common defective pathway, leading to disturbances in the neuronal growth cone and cytoskeleton. Encouraged by the evidence of this defected pathway, we analyzed the molecular interactions of NCL-proteins and observed that Cln5 and Cln1/Ppt1 proteins interact with each other. Furthermore, we demonstrated that Cln5 and Cln1/Ppt1 share an interaction partner, the F1-ATP synthase, potentially linking both vLINCLFIN and INCL diseases to disturbed lipid metabolism. In addition, Cln5 was shown to interact with other NCL proteins; Cln2, Cln3, Cln6 and Cln8, implicating a central role for Cln5 in the NCL pathophysiology. This study is the first to describe the brain pathology and gene expression changes in the Cln5-/- mouse. Together the findings presented in this thesis represent novel information of the disease processes and the molecular mechanisms behind vLINCLFin and have highlighted that vLINCLFin forms a very important model to analyze the pathophysiology of NCL diseases.

Tracking and identifying wastewater toxicants and assessing their biodegradation products

Screening of wastewater effluents from municipal and industrial wastewater treatment plants with biotests showed that the treated wastewater effluents possess only minor acute toxic properties towards whole organisms (e.g. bacteria, algae, daphnia), if any. In vitro tests (sub-mitochondrial membranes and fish hepatocytes) were generally more susceptible to the effluents. Most of the effluents indicated the presence of hormonally active compounds, as the production of vitellogenin, an egg yolk precursor protein, was induced in fish hepatocytes exposed to wastewater. In addition, indications of slight genotoxic potential was found in one effluent concentrate with a recombinant bacteria test. Reverse electron transport (RET) of mitochondrial membranes was used as a model test to conduct effluent assessment followed by toxicant characterisations and identifications. Using a modified U.S. EPA Toxicity Identification Evaluation Phase I scheme and additional case-specific methods, the main compound in a pulp and paper mill effluent causing RET inhibition was characterised to be an organic, relatively hydrophilic high molecular weight (HMW) compound. The toxicant could be verified as HMW lignin by structural analyses using nuclear magnetic resonance. In the confirmation step commercial and in-house extracted lignin products were used. The possible toxicity related structures were characterised by statistical analysis of the chemical breakdown structures of laboratory-scale pulping and bleaching effluents and the toxicities of these effluents. Finally, the biological degradation of the identified toxicant and other wastewater constituents was evaluated using bioassays in combination with chemical analyses. Biological methods have not been used routinely in establishing effluent discharge limits in Finland. However, the biological effects observed in this study could not have been predicted using only routine physical and chemical effluent monitoring parameters. Therefore chemical parameters cannot be considered to be sufficient in controlling effluent discharges especially in case of unknown, possibly bioaccumulative, compounds that may be present in small concentrations and may cause chronic effects.

Semantic Classes in Topic Detection and Tracking

Topic detection and tracking (TDT) is an area of information retrieval research the focus of which revolves around news events. The problems TDT deals with relate to segmenting news text into cohesive stories, detecting something new, previously unreported, tracking the development of a previously reported event, and grouping together news that discuss the same event. The performance of the traditional information retrieval techniques based on full-text similarity has remained inadequate for online production systems. It has been difficult to make the distinction between same and similar events. In this work, we explore ways of representing and comparing news documents in order to detect new events and track their development. First, however, we put forward a conceptual analysis of the notions of topic and event. The purpose is to clarify the terminology and align it with the process of news-making and the tradition of story-telling. Second, we present a framework for document similarity that is based on semantic classes, i.e., groups of words with similar meaning. We adopt people, organizations, and locations as semantic classes in addition to general terms. As each semantic class can be assigned its own similarity measure, document similarity can make use of ontologies, e.g., geographical taxonomies. The documents are compared class-wise, and the outcome is a weighted combination of class-wise similarities. Third, we incorporate temporal information into document similarity. We formalize the natural language temporal expressions occurring in the text, and use them to anchor the rest of the terms onto the time-line. Upon comparing documents for event-based similarity, we look not only at matching terms, but also how near their anchors are on the time-line. Fourth, we experiment with an adaptive variant of the semantic class similarity system. The news reflect changes in the real world, and in order to keep up, the system has to change its behavior based on the contents of the news stream. We put forward two strategies for rebuilding the topic representations and report experiment results. We run experiments with three annotated TDT corpora. The use of semantic classes increased the effectiveness of topic tracking by 10-30\% depending on the experimental setup. The gain in spotting new events remained lower, around 3-4\%. The anchoring the text to a time-line based on the temporal expressions gave a further 10\% increase the effectiveness of topic tracking. The gains in detecting new events, again, remained smaller. The adaptive systems did not improve the tracking results.

Measuring and tracking quality factors in Free and Open Source Software projects

Free and Open Source Software (FOSS) has gained increased interest in the computer software industry, but assessing its quality remains a challenge. FOSS development is frequently carried out by globally distributed development teams, and all stages of development are publicly visible. Several product and process-level quality factors can be measured using the public data. This thesis presents a theoretical background for software quality and metrics and their application in a FOSS environment. Information available from FOSS projects in three information spaces are presented, and a quality model suitable for use in a FOSS context is constructed. The model includes both process and product quality metrics, and takes into account the tools and working methods commonly used in FOSS projects. A subset of the constructed quality model is applied to three FOSS projects, highlighting both theoretical and practical concerns in implementing automatic metric collection and analysis. The experiment shows that useful quality information can be extracted from the vast amount of data available. In particular, projects vary in their growth rate, complexity, modularity and team structure.

The community of medium-sized carnivores: the interactions between species, habitats and rabies

The composition of the carnivore community influences the different forms of inter-specific interactions. Furthermore, inter-specific interactions of carnivores have important implications for intra-guild competition, epidemiology and strategies of species-specific population management. Zoonooses, such as rabies, are diseases that can be transmitted from wildlife to people. Knowing the ecological characteristics of the species helps us to choose the right preventive actions and to time them accurately. In this thesis, I have studied how raccoon dogs Nyctereutes procyonoides, European badgers Meles meles, red foxes Vulpes vulpes and domestic cats Felis silvestris catus act as members of carnivore community, and how these interactions relate to the transmission risk of rabies. In the study area, these species form a community of medium-sized and rather generalist predators. They live in the same areas, in spatially and temporally overlapping home ranges and use the same habitats and dens and even have similar diets. However, there is no direct evidence of competition. Shared dens point to good tolerance of other species. Numerous observations of animals moving in each other’s proximity give similar clues. However, overlapping home ranges and similar habitat preferences lead to frequent inter-specific contacts, which increase the risk of possible rabies transmission. Also, the new insight of habitat use gained by this study illustrates the similar favouring of deciduous forests and fields by these sympatric medium-sized carnivores, creating a basis for contact zones, i.e. risky habitats for rabies transmission and spread. This study is so far the only simultaneous radio tracking study of raccoon dogs, badgers, foxes and cats. These results give new insight of the interactions in the carnivore community, as well as of the behaviour of each individual species. Also, these results have significant implications for the planning of rabies control. In order to reach viable management decisions, not only one or two species should be taken into consideration, but the whole community. In particular, this changes the perspective to inter-specific contacts, animal densities, densities of individuals susceptible to diseases and the magnitude of preventive actions. Rabies should be considered as a multi-vector disease, at least in Finland and the Baltic states. It is of interest for disease management to be able to model an epizootic with local parameters to reflect the real situation and also to suite best the local management needs.

Measurements of the top-quark mass using charged particle tracking

We present three measurements of the top-quark mass in the lepton plus jets channel with approximately 1.9 fb-1 of integrated luminosity collected with the CDF II detector using quantities with minimal dependence on the jet energy scale. One measurement exploits the transverse decay length of b-tagged jets to determine a top-quark mass of 166.9+9.5-8.5 (stat) +/- 2.9 (syst) GeV/c2, and another the transverse momentum of electrons and muons from W-boson decays to determine a top-quark mass of 173.5+8.8-8.9 (stat) +/- 3.8 (syst) GeV/c2. These quantities are combined in a third, simultaneous mass measurement to determine a top-quark mass of 170.7 +/- 6.3 (stat) +/- 2.6 (syst) GeV/c2.

Alignment of the ALICE Inner Tracking System with cosmic-ray tracks

ALICE (A Large Ion Collider Experiment) is the LHC (Large Hadron Collider) experiment devoted to investigating the strongly interacting matter created in nucleus-nucleus collisions at the LHC energies. The ALICE ITS, Inner Tracking System, consists of six cylindrical layers of silicon detectors with three different technologies; in the outward direction: two layers of pixel detectors, two layers each of drift, and strip detectors. The number of parameters to be determined in the spatial alignment of the 2198 sensor modules of the ITS is about 13,000. The target alignment precision is well below 10 micron in some cases (pixels). The sources of alignment information include survey measurements, and the reconstructed tracks from cosmic rays and from proton-proton collisions. The main track-based alignment method uses the Millepede global approach. An iterative local method was developed and used as well. We present the results obtained for the ITS alignment using about 10^5 charged tracks from cosmic rays that have been collected during summer 2008, with the ALICE solenoidal magnet switched off.

Measurements of the top-quark mass using charged particle tracking

We present three measurements of the top-quark mass in the lepton plus jets channel with approximately 1.9 fb-1 of integrated luminosity collected with the CDF II detector using quantities with minimal dependence on the jet energy scale. One measurement exploits the transverse decay length of b-tagged jets to determine a top-quark mass of 166.9+9.5-8.5 (stat) +/- 2.9 (syst) GeV/c2, and another the transverse momentum of electrons and muons from W-boson decays to determine a top-quark mass of 173.5+8.8-8.9 (stat) +/- 3.8 (syst) GeV/c2. These quantities are combined in a third, simultaneous mass measurement to determine a top-quark mass of 170.7 +/- 6.3 (stat) +/- 2.6 (syst) GeV/c2.

Cattle Teeth in Graves : Interpretations of animal bones found in Finnish inhumation graves (ca AD 550-1700)

The nature of a burial is always ritualistic. This is often forgotten when dealing with Finnish inhumation burials containing animal bones. Only the animal bones found close to the deceased have traditionally been thought to have a ritualistic purpose. The animal bones found in the filling of the grave, which is still part of the burial, has on the other hand, often been neglected in the previous research. In this Master s thesis I will discuss the function and interpretation of animal bones in graves. The base of this study is six sites, all of different nature, from Finland. Luistari in Eura is from the western coast and is dated to Late Iron Age (and possibly Medieval period), the Medieval hamlet of Finno is situated in Espoo which is situated on the southern coast. Two town burials, Turku and Porvoo, are also included in this study. The graves from Turku are dated to Late Medieval period and Early Renaissance, whereas the cemetery in Porvoo is from the 18th century. Visulahti in Mikkeli is from the Late Iron Age and represents Eastern Finnish burial tradition, the same as Suotniemi from Käkisalmi parish, which is nowadays part of Russia. While parts of the animal bones had already been analysed before, the author also analysed animal bones for the purpose of the present Master´s thesis. The bones were compared to the burial contexts, when possible. Based on the comparisons I have made interpretations which might explain the existence of animal bones in the graves. The interpretations are among others sacrifice, commemoration meals and animal burials. The site could also have been a settlement site prior to the graves, thus the bones in the graves would belong to the settlement phase. When comparing the date of the studied sites, the town burials are later and the animal bones are probably related to previous or contemporary use of the sites as graveyards. On top of this there does not seem to be much difference in burial tradition between Eastern and Western Finland, although at least from the hamlet burials of Finno there are aspects that could be linked to Eastern burials. In making the interpretations I have taken into consideration the aspects of belief during different time periods when they could be accounted as relevant. Also the problems with bone preservation were relevant and challenging for the study. Often only the hardest substance of the skeleton, namely teeth, has been preserved. For this reason the quality of the archaeological documentation was a key issue in this study. In producing quality interpretations of the animal bones in graves, the bones, contexts and their relationship to the surrounding site should be documented with care.

Investigating online reading with eye tracking and EEG : The influence of text format, reading task and parafoveal stimuli on reading processes

Research on reading has been successful in revealing how attention guides eye movements when people read single sentences or text paragraphs in simplified and strictly controlled experimental conditions. However, less is known about reading processes in more naturalistic and applied settings, such as reading Web pages. This thesis investigates online reading processes by recording participants eye movements. The thesis consists of four experimental studies that examine how location of stimuli presented outside the currently fixated region (Study I and III), text format (Study II), animation and abrupt onset of online advertisements (Study III), and phase of an online information search task (Study IV) affect written language processing. Furthermore, the studies investigate how the goal of the reading task affects attention allocation during reading by comparing reading for comprehension with free browsing, and by varying the difficulty of an information search task. The results show that text format affects the reading process, that is, vertical text (word/line) is read at a slower rate than a standard horizontal text, and the mean fixation durations are longer for vertical text than for horizontal text. Furthermore, animated online ads and abrupt ad onsets capture online readers attention and direct their gaze toward the ads, and distract the reading process. Compared to a reading-for-comprehension task, online ads are attended to more in a free browsing task. Moreover, in both tasks abrupt ad onsets result in rather immediate fixations toward the ads. This effect is enhanced when the ad is presented in the proximity of the text being read. In addition, the reading processes vary when Web users proceed in online information search tasks, for example when they are searching for a specific keyword, looking for an answer to a question, or trying to find a subjectively most interesting topic. A scanning type of behavior is typical at the beginning of the tasks, after which participants tend to switch to a more careful reading state before finishing the tasks in the states referred to as decision states. Furthermore, the results also provided evidence that left-to-right readers extract more parafoveal information to the right of the fixated word than to the left, suggesting that learning biases attentional orienting towards the reading direction.