JNK regulation of neurogenesis, neuroplasticity and anxiety-related behaviors in mice

I vår moderna värld har förekomsten av ångeststörningar drastiskt ökat, vilket påverkar välfärden i våra samhällen. Eftersom de molekylära mekanismerna bakom ångest är relativt okända, är möjligheterna till behandling av ångeststörningar begränsade. I och med utvecklingen av genetiska manipuleringmetoder och avbildningstekniker har strukturella förändringar associerade med ångeststörningar kunnat konstateras. Neuroanatomiska studier har påvisat störningar i dendritarkitektur, dendrittaggar och i neurogenesen hos vuxna individer. Särskilt neurogenesen i hippocampus anses viktig i detta sammanhang. Neurogenes i hippocampus har föreslagits spela en viktig roll i ångeststörningarnas patofysiologi och för hur vissa antidepressiva läkemedel förmedlar sin effekt. Under senare år har MAP-kinaser (MAPK) föreslagits vara involverade både i uppkomsten av affektiva störningar och i neurogenes i hippocampus. JNK är en grupp kinaser inom MAPK-familjen som aktiveras av olika externa stressfaktorer. I normala celler är aktiviteten hos JNK låg. Cell-stress ökar aktiviteten hos JNK vilket leder till bl.a. apoptos. JNK kinaser anses vara potentiella terapeutiska mål för behandling av neurodegenerativa sjukdomar men deras potential som mål för behandling av affektiva sjukdomar har tillsvidare inte utretts. Den här avhandlingen behandlar betydelsen av JNK för ångestrelaterat beteende hos möss. Med hjälp av Jnk1-knockout möss och farmakologisk inhibering av JNK-signalering, demonstreras att JNK reglerar neurogenes i hippocampus, vilket i sin tur ligger bakom mössens ångestrelaterade beteende. Jnk1-knockout möss var mindre ängsliga och uppvisade ökad neurogenes i hippcampus jämfört med kontrollmöss. Inhibering av JNK-signalering i hjärnan hos möss gjorde dem också mindre ängsliga och ökade neurogenesen i hippocampus på samma sätt som vissa antidepressiva läkemedel. Inhibering av JNK-aktivitet ledde inte bara till ökad neurogenes i hippocampus, utan främjade också mognandet av nybildade nervceller hos vuxna möss. Resultaten visar också att dendritarkitekturen och fördelningen av dendrittaggar hos CA3 neuroner i hippocampus är förändrad hos Jnk1-knockout möss. Genom screening av substratmolekyler för JNK hittades två JNKeffektormolekyler, MARCKSL1 (ett aktin-associerat protein) och MAP2 (ett mikrotubulus-associerat protein), som reglerade neuronernas sttruktur. Det här tyder på att JNK-signalering kan kontrollera ångeststörningsrelaterade förändringar hor dendriter och dendrittaggar. Sammanfattningsvis ger resultaten som presenteras i avhandlingen en ökad insikt i molekylära mekanismer som kan leda till ångeststörningsrelaterade förändringar i neurogenes och dendritstruktur. Därtill föreslås att JNKsignalbanan har potential som terapeutiskt mål för behandling av ångeststörningar.

University students’ regulation of learning and text processing – examples from medical and teacher education

The general aim of the thesis was to study university students’ learning from the perspective of regulation of learning and text processing. The data were collected from the two academic disciplines of medical and teacher education, which share the features of highly scheduled study, a multidisciplinary character, a complex relationship between theory and practice and a professional nature. Contemporary information society poses new challenges for learning, as it is not possible to learn all the information needed in a profession during a study programme. Therefore, it is increasingly important to learn how to think and learn independently, how to recognise gaps in and update one’s knowledge and how to deal with the huge amount of constantly changing information. In other words, it is critical to regulate one’s learning and to process text effectively. The thesis comprises five sub-studies that employed cross-sectional, longitudinal and experimental designs and multiple methods, from surveys to eye tracking. Study I examined the connections between students’ study orientations and the ways they regulate their learning. In total, 410 second-, fourth- and sixth-year medical students from two Finnish medical schools participated in the study by completing a questionnaire measuring both general study orientations and regulation strategies. The students were generally deeply oriented towards their studies. However, they regulated their studying externally. Several interesting and theoretically reasonable connections between the variables were found. For instance, self-regulation was positively correlated with deep orientation and achievement orientation and was negatively correlated with non-commitment. However, external regulation was likewise positively correlated with deep orientation and achievement orientation but also with surface orientation and systematic orientation. It is argued that external regulation might function as an effective coping strategy in the cognitively loaded medical curriculum. Study II focused on medical students’ regulation of learning and their conceptions of the learning environment in an innovative medical course where traditional lectures were combined wth problem-based learning (PBL) group work. First-year medical and dental students (N = 153) completed a questionnaire assessing their regulation strategies of learning and views about the PBL group work. The results indicated that external regulation and self-regulation of the learning content were the most typical regulation strategies among the participants. In line with previous studies, self-regulation wasconnected with study success. Strictly organised PBL sessions were not considered as useful as lectures, although the students’ views of the teacher/tutor and the group were mainly positive. Therefore, developers of teaching methods are challenged to think of new solutions that facilitate reflection of one’s learning and that improve the development of self-regulation. In Study III, a person-centred approach to studying regulation strategies was employed, in contrast to the traditional variable-centred approach used in Study I and Study II. The aim of Study III was to identify different regulation strategy profiles among medical students (N = 162) across time and to examine to what extent these profiles predict study success in preclinical studies. Four regulation strategy profiles were identified, and connections with study success were found. Students with the lowest self-regulation and with an increasing lack of regulation performed worse than the other groups. As the person-centred approach enables us to individualise students with diverse regulation patterns, it could be used in supporting student learning and in facilitating the early diagnosis of learning difficulties. In Study IV, 91 student teachers participated in a pre-test/post-test design where they answered open-ended questions about a complex science concept both before and after reading either a traditional, expository science text or a refutational text that prompted the reader to change his/her beliefs according to scientific beliefs about the phenomenon. The student teachers completed a questionnaire concerning their regulation and processing strategies. The results showed that the students’ understanding improved after text reading intervention and that refutational text promoted understanding better than the traditional text. Additionally, regulation and processing strategies were found to be connected with understanding the science phenomenon. A weak trend showed that weaker learners would benefit more from the refutational text. It seems that learners with effective learning strategies are able to pick out the relevant content regardless of the text type, whereas weaker learners might benefit from refutational parts that contrast the most typical misconceptions with scientific views. The purpose of Study V was to use eye tracking to determine how third-year medical studets (n = 39) and internal medicine residents (n = 13) read and solve patient case texts. The results revealed differences between medical students and residents in processing patient case texts; compared to the students, the residents were more accurate in their diagnoses and processed the texts significantly faster and with a lower number of fixations. Different reading patterns were also found. The observed differences between medical students and residents in processing patient case texts could be used in medical education to model expert reasoning and to teach how a good medical text should be constructed. The main findings of the thesis indicate that even among very selected student populations, such as high-achieving medical students or student teachers, there seems to be a lot of variation in regulation strategies of learning and text processing. As these learning strategies are related to successful studying, students enter educational programmes with rather different chances of managing and achieving success. Further, the ways of engaging in learning seldom centre on a single strategy or approach; rather, students seem to combine several strategies to a certain degree. Sometimes, it can be a matter of perspective of which way of learning can be considered best; therefore, the reality of studying in higher education is often more complicated than the simplistic view of self-regulation as a good quality and external regulation as a harmful quality. The beginning of university studies may be stressful for many, as the gap between high school and university studies is huge and those strategies that were adequate during high school might not work as well in higher education. Therefore, it is important to map students’ learning strategies and to encourage them to engage in using high-quality learning strategies from the beginning. Instead of separate courses on learning skills, the integration of these skills into course contents should be considered. Furthermore, learning complex scientific phenomena could be facilitated by paying attention to high-quality learning materials and texts and other support from the learning environment also in the university. Eye tracking seems to have great potential in evaluating performance and growing diagnostic expertise in text processing, although more research using texts as stimulus is needed. Both medical and teacher education programmes and the professions themselves are challenging in terms of their multidisciplinary nature and increasing amounts of information and therefore require good lifelong learning skills during the study period and later in work life.

Real-time monitoring of laser scribing process utilizing high-speed camera

Currently, laser scribing is growing material processing method in the industry. Benefits of laser scribing technology are studied for example for improving an efficiency of solar cells. Due high-quality requirement of the fast scribing process, it is important to monitor the process in real time for detecting possible defects during the process. However, there is a lack of studies of laser scribing real time monitoring. Commonly used monitoring methods developed for other laser processes such a laser welding, are sufficient slow and existed applications cannot be implemented in fast laser scribing monitoring. The aim of this thesis is to find a method for laser scribing monitoring with a high-speed camera and evaluate reliability and performance of the developed monitoring system with experiments. The laser used in experiments is an IPG ytterbium pulsed fiber laser with 20 W maximum average power and Scan head optics used in the laser is Scanlab’s Hurryscan 14 II with an f100 tele-centric lens. The camera was connected to laser scanner using camera adapter to follow the laser process. A powerful fully programmable industrial computer was chosen for executing image processing and analysis. Algorithms for defect analysis, which are based on particle analysis, were developed using LabVIEW system design software. The performance of the algorithms was analyzed by analyzing a non-moving image from the scribing line with resolution 960x20 pixel. As a result, the maximum analysis speed was 560 frames per second. Reliability of the algorithm was evaluated by imaging scribing path with a variable number of defects 2000 mm/s when the laser was turned off and image analysis speed was 430 frames per second. The experiment was successful and as a result, the algorithms detected all defects from the scribing path. The final monitoring experiment was performed during a laser process. However, it was challenging to get active laser illumination work with the laser scanner due physical dimensions of the laser lens and the scanner. For reliable error detection, the illumination system is needed to be replaced.

Variable-speed-drive-based detection methods for problems in fluid handling systems

Fluid handling systems account for a significant share of the global consumption of electrical energy. They also suffer from problems, which reduce their energy efficiency and increase life-cycle costs. Detecting or predicting these problems in time can make fluid handling systems more environmentally and economically sustainable to operate. In this Master’s Thesis, significant problems in fluid systems were studied and possibilities to develop variable-speed-drive-based detection methods for them was discussed. A literature review was conducted to find significant problems occurring in fluid handling systems containing pumps, fans and compressors. To find case examples for evaluating the feasibility of variable-speed-drive-based methods, queries were sent to industrial companies. As a result of this, the possibility to detect heat exchanger fouling with a variable-speed drive was analysed with data from three industrial cases. It was found that a mass flow rate estimate, which can be generated with a variable speed drive, can be used together with temperature measurements to monitor a heat exchanger’s thermal performance. Secondly, it was found that the fouling-related increase in the pressure drop of a heat exchanger can be monitored with a variable speed drive. Lastly, for systems where the flow device is speed controlled with by a pressure measurement, it was concluded that increasing rotational speed can be interpreted as progressing fouling in the heat exchanger.

Design and Material Selection of High-Speed Rotating Electrical Machines

The increasing emphasis on energy efficiency is starting to yield results in the reduction in greenhouse gas emissions; however, the effort is still far from sufficient. Therefore, new technical solutions that will enhance the efficiency of power generation systems are required to maintain the sustainable growth rate, without spoiling the environment. A reduction in greenhouse gas emissions is only possible with new low-carbon technologies, which enable high efficiencies. The role of the rotating electrical machine development is significant in the reduction of global emissions. A high proportion of the produced and consumed electrical energy is related to electrical machines. One of the technical solutions that enables high system efficiency on both the energy production and consumption sides is high-speed electrical machines. This type of electrical machines has a high system overall efficiency, a small footprint, and a high power density compared with conventional machines. Therefore, high-speed electrical machines are favoured by the manufacturers producing, for example, microturbines, compressors, gas compression applications, and air blowers. High-speed machine technology is challenging from the design point of view, and a lot of research is in progress both in academia and industry regarding the solution development. The solid technical basis is of importance in order to make an impact in the industry considering the climate change. This work describes the multidisciplinary design principles and material development in high-speed electrical machines. First, high-speed permanent magnet synchronous machines with six slots, two poles, and tooth-coil windings are discussed in this doctoral dissertation. These machines have unique features, which help in solving rotordynamic problems and reducing the manufacturing costs. Second, the materials for the high-speed machines are discussed in this work. The materials are among the key limiting factors in electrical machines, and to overcome this limit, an in-depth analysis of the material properties and behavior is required. Moreover, high-speed machines are sometimes operating in a harsh environment because they need to be as close as possible to the rotating tool and fully exploit their advantages. This sets extra requirements for the materials applied.

Effects of bank supervision and regulation on bank risk

In the last few decades, banking has strongly internationalized and become more complex. Hence, bank supervision and regulation has taken global perspective, too. The most important international regulation are the Basel frameworks by the Basel committee on banking supervision. This study examines the effects of bank supervision and regulation, especially the Basel II, on bank risk and risk-taking. In order to separate and recognize the efficiency of these effects, the co-effects of many supervisory and regulatory tools together with other relevant factors must be taken into account. The focus of the study is on the effects of asymmetric information and banking procyclicality on the efficiency of the Basel II. This study tries to find an answer, if the Basel II, implemented in 2008, has decreased bank risk in banks of European Union member states. This study examines empirically, if the volatility on bank stock returns have changed after the implementation of the Basel II. Panel data consists of 62 bank stock returns, bank-specific variables, economic variables and variables concerning regulatory environment between 2003 and 2011. Fixed effects regression is used for panel data analysis. Results indicate that volatility on bank stock returns has increased after 2008 and the implementation of the Basel II. Result is statistically very significant and robustness has been verified in different model specifications. The result of this study contradicts with the goal of the Basel II about banking system stability. Banking procyclicality and wrong incentives for regulatory arbitrage under asymmetric information explained in theoretical part may explain this result. On the other hand, simultaneously with the implementation of the Basel II, the global financial crisis emerged and caused severe losses in banks and increased stock volatility. However, it is clear that supervision and regulation was unable to prevent the global financial crisis. After the financial crisis, supervision and regulation have been reformed globally. The main problems of the Basel II, examined in the theoretical part, have been recognized in order to prevent problems of procyclicality and wrong incentives in the future.

The mechanism of the regulation of energy distribution between photosystems 1 and 2 in the cyanobacterium Synechococcus sp. strain PCC 7002 /

Cyanobacteria are able to regulate the distribution of absorbed light energy between photo systems 1 and 2 in response to light conditions. The mechanism of this regulation (the state transition) was investigated in the marine cyanobacterium Synechococcus sp. strain PCC 7002. Three cell types were used: the wild type, psaL mutant (deletion of a photo system 1 subunit thought to be involved in photo system 1 trimerization) and the apcD mutant (a deletion of a phycobilisome subunit thought to be responsible for energy transfer to photo system 1). Evidence from 77K fluorescence emission spectroscopy, room temperature fluorescence and absorption cross-section measurements were used to determine a model of energy distribution from the phycobilisome and chlorophyll antennas in state 1 and state 2. The data confirm that in state 1 the phycobilisome is primarily attached to PS2. In state 2, a portion of the phycobilisome absorbed light energy is redistributed to photo system 1. This energy is directly transferred to photo system 1 by one of the phycobilisome terminal emitters, the product of the apcD gene, rather than via the photo system 2 chlorophyll antenna by spillover (energy transfer between the photo system 2 and photo system 1 chlorophyll antenna). The data also show that energy absorbed by the photo system 2 chlorophyll antenna is redistributed to photo system 1 in state 2. This could occur in one of two ways; by spillover or in a way analogous to higher plants where a segment of the chlorophyll antenna is dissociated from photo system 2 and becomes part of the photo system 1 antenna. The presence of energy transfer between neighbouring photo system 2 antennae was determined at both the phycobilisome and chlorophyll level, in states 1 and 2. Increases in antenna absorption cross-section with increasing reaction center closure showed that there is energy transfer (connectivity) between photosystem 2 antennas. No significant difference was shown in the amount of connectivity under these four conditions.

Predicting performance on fluid intelligence from speed of processing, working memory, and controlled attention

Fluid inteliigence has been defined as an innate ability to reason which is measured commonly by the Raven's Progressive Matrices (RPM). Individual differences in fluid intelligence are currently explained by the Cascade model (Fry & Hale, 1996) and the Controlled Attention hypothesis (Engle, Kane, & Tuholski, 1999; Kane & Engle, 2002). The first theory is based on a complex relation among age, speed, and working memory which is described as a Cascade. The alternative to this theory, the Controlled Attention hypothesis, is based on the proposition that it is the executive attention component of working memory that explains performance on fluid intelligence tests. The first goal of this study was to examine whether the Cascade model is consistent within the visuo-spatial and verbal-numerical modalities. The second goal was to examine whether the executive attention component ofworking memory accounts for the relation between working memory and fluid intelligence. Two hundred and six undergraduate students between the ages of 18 and 28 completed a battery of cognitive tests selected to measure processing speed, working memory, and controlled attention which were selected from two cognitive modalities, verbalnumerical and visuo-spatial. These were used to predict performance on two standard measures of fluid intelligence: the Raven's Progressive Matrices (RPM) and the Shipley Institute of Living Scales (SILS) subtests. Multiple regression and Structural Equation Modeling (SEM) were used to test the Cascade model and to determine the independent and joint effects of controlled attention and working memory on general fluid intelligence. Among the processing speed measures only spatial scan was related to the RPM. No other significant relations were observed between processing speed and fluid intelligence. As 1 a construct, working memory was related to the fluid intelligence tests. Consistent with the predictions for the RPM there was support for the Cascade model within the visuo-spatial modality but not within the verbal-numerical modality. There was no support for the Cascade model with respect to the SILS tests. SEM revealed that there was a direct path between controlled attention and RPM and between working memory and RPM. However, a significant path between set switching and RPM explained the relation between controlled attention and RPM. The prediction that controlled attention mediated the relation between working memory and RPM was therefore not supported. The findings support the view that the Cascade model may not adequately explain individual differences in fluid intelligence and this may be due to the differential relations observed between working memory and fluid intelligence across different modalities. The findings also show that working memory is not a domain-general construct and as a result its relation with fluid intelligence may be dependent on the nature of the working memory modality.

The influence of skeletal muscle cell volume on the regulation of carbohydrate uptake and muscle metabolism

This study investigated the regulation of carbohydrate metabolism and glucose uptake through changes in skeletal muscle cell volume. Using an established invitro isolated whole muscle model, soleus (SOL) and extensor digitorum longus (EDL) muscles were dissected from male rats and incubated in an organ bath containing Sigma medium-199 with 8 mM D-glucose altered to target osmolality (hypo-osmotic: HYPO, iso-osmotic: ISO, hyper-osmotic: HYPER; 190, 290, 400 mmol/kg). Muscles were divided into two groups; metabolite (MM) and uptake (MU). MM (N=48) were incubated for 60 minutes and were then immediately flash frozen. MU (N=24) were incubated for 30 minutes and then the extracellular fluid was exchanged for media containing ^H-glucose and ^'*C-mannitol and incubated for another 30 minutes. After the incubation, the muscles were freeze clamped. Results demonstrated a relative water decrease and increase in HYPER and HYPO, respectively. EDL and SOL glucose uptakes were found to be significantly greater in HYPER conditions. The HYPER condition resulted in significant alterations in muscle metabolite concentrations (lower glycogen, elevated lactate, and G-6-P) suggesting a catabolic cell state, and an increase in glycogen synthase transformation when compared to the HYPO group. In conclusion, skeletal muscle cell volume alters rates of glucose uptake with further alterations in muscle metabolites and glycogen synthase transformation.

The effects of R(+)-lipoic acid supplementation on regulation of human skeletal muscle pyruvate dehydrogenase

This thesis investigated whole body glucose disposal and the adaptive changes in skeletal muscle carbohydrate metabolism following 28 d of supplementation with 1000 mg R(+)-lipoic acid in young sedentary males (age, 22.1 ± 0.67 yr, body mass, 78.7 ± 10.3 kg, n=9). In certain individuals, lipoic acid decreased the 180-min area under the glucose concentration and insulin concentration curve during an oral glucose tolerance test (OGTT) (n=4). In the same individuals, lipoic acid supplementation decreased pyruvate dehydrogenase kinase activity (PDK) (0.09 ± 0.024 min"^ vs. 0.137 ± 0.023 min'\ n=4). The fasting levels of the activated form of pyruvate dehydrogenase (PDHa) were decreased following lipoic acid (0.42 ± 0.13 mmol-min'kg'^ vs. 0.82 ± 0.32 mmolrnin'^kg"\ n=4), yet increased to a greater extent during the OGTT (1.21 ± 0.34 mmol-min'kg"' vs. 0.81 ±0.13 mmolmin"'kg'\ n=4) following hpoic acid supplementation. No changes were demonstrated in the remaining subjects (n=5). It was concluded that improved glucose clearance during an OGTT following lipoic acid supplementation is assisted by increased muscle glucose oxidation through increased PDHa activation and decreased PDK activity in certain individuals.

Openness and privacy in Ontario: an evaluation of the implementation of FIPPA : (The Freedom of Information and Protection of Privacy Act, 1987, Chapter 25 and Ontario Regulation 532/87) /

Since the early 1970's, Canadians have expressed many concerns about the growth of government and its impact on their daily lives. The public has requested increased access to government documents and improved protection of the personal information which is held in government files and data banks. At the same time, both academics and practitioners in the field of public administration have become more interested in the values that public servants bring to their decisions and recommendations. Certain administrative values, such as accountability and integrity, have taken on greater relative importance. The purpose of this thesis is to examine the implementation of Ontario's access and privacy law. It centres on the question of whether or not the Freedom of Information and Protection of Privacy Act, 1987, (FIPPA) has answered the demand for open access to government while at the same time protecting the personal privacy of individual citizens. It also assesses the extent to which this relatively new piece of legislation has made a difference to the people of Ontario. The thesis presents an overview of the issues of freedom of information and protection of privacy in Ontario. It begins with the evolution of the legislation and a description of the law itself. It focuses on the structures and processes which have been established to meet the procedural and administrative demands of the Act. These structures and processes are evaluated in two ways. First, the thesis evaluates how open the Ontario government has become and, second, it determines how Ill carefully the privacy rights of individuals are safeguarded. An analytical framework of administrative values is used to evaluate the overall performance of the government in these two areas. The conclusion is drawn that, overall, the Ontario government has effectively implemented the Freedom of Information and Protection of Privacy Act, particularly by providing access to most government-held documents. The protection of individual privacy has proved to be not only more difficult to achieve, but more difficult to evaluate. However, the administrative culture of the Ontario bureaucracy is shown to be committed to ensuring that the access and privacy rights of citizens are respected.

Influence of temperature and photoperiod upon ionic regulation in rainbow trout Salmo gairdneri

Interactions of photoperiod and temperature upon waterelectrolyte balance were examined in rainbow trout acclimated to six combinations of two photoperiods {18h light: 6h dark, o 6h light: l8h dark) and three temperatures (2, 10 and 18 C). The influence of temperature and photoperiod upon plasma, skeletal muscle, cardiac muscle and liver levels of sodium, potassium, magnesi.um, calcium, chloride, water content, water distribution and cellular ion concentrations was determined by a one way analysis of variance. Significant (p < 0.05 or better) temperature effects at common photoperiods were observed in 70% of the analyses performed, showing no bias toward either photoperiod. Significant photoperiod effects occured in 57% of the analyses performed at common temperatures. The influence of photoperiod was most prevalent at reduced temperatures. Potassium and magnesium appeared to be particularly thermosensitive, while sodium and calcium were the most photosensitive of the electrolytes. The ionic composition of all tissues studied were relatively thermosensitive, with liver apparently being the most sensitive. On the other hand; the ionic composition of skeletal and cardiac muscle appear to be the mos.t photosensitive of the tissues examined. Water content and distribution in skeletal muscle and liver were significantly influenced by temperature in 50% of the analyses performed showing a very strong bias toward UwinterU animals. Photoperiod effects were significant in 56% of the water parameters measured with a strong bias toward the two lower temperatures. Body weight was of significant influence in 16% of the 174 analyses performed. These data are discussed in terms of the effect of temperature upon ionregulatory mechanisms and the possible impact of photoperiod variations on endocrine systems influencing water-electrolyte metabolism.