Generation and Characterization of Knockout Mice and Analysis of Patient Material Demonstrates a Role for Tissue Inhibitor of Metalloproteinases 4 (Timp4) in the Cardiovascular System and Tumor Metastasis

This thesis focuses on tissue inhibitor of metalloproteinases 4 (TIMP4) which is the newest member of a small gene and protein family of four closely related endogenous inhibitors of extracellular matrix (ECM) degrading enzymes. Existing data on TIMP4 suggested that it exhibits a more restricted expression pattern than the other TIMPs with high expression levels in heart, brain, ovary and skeletal muscle. These observations and the fact that the ECM is of special importance to provide the cardiovascular system with structural strength combined with elasticity and distensibility, prompted the present molecular biologic investigation on TIMP4. In the first part of the study the murine Timp4 gene was cloned and characterized in detail. The structure of murine Timp4 genomic locus resembles that in other species and of the other Timps. The highest Timp4 expression was detected in heart, ovary and brain. As the expression pattern of Timp4 gives only limited information about its role in physiology and pathology, Timp4 knockout mice were generated next. The analysis of Timp4 knockout mice revealed that Timp4 deficiency has no obvious effect on the development, growth or fertility of mice. Therefore, Timp4 deficient mice were challenged using available cardiovascular models, i.e. experimental cardiac pressure overload and myocardial infarction. In the former model, Timp4 deficiency was found to be compensated by Timp2 overexpression, whereas in the myocardial infarct model, Timp4 deficiency resulted in increased mortality due to increased susceptibility for cardiac rupture. In the wound healing model, Timp4 deficiency was shown to result in transient retardation of re-epithelialization of cutaneous wounds. Melanoma tumor growth was similar in Timp4 deficient and control mice. Despite of this, lung metastasis of melanoma cells was significantly increased in Timp4 null mice. In an attempt to translate the current findings to patient material, TIMP4 expression was studied in human specimens representing different inflammatory cardiovascular pathologies, i.e. giant cell arteritis, atherosclerotic coronary arteries and heart allografts exhibiting signs of chronic rejection. The results showed that cardiovascular expression of TIMP4 is elevated particularly in areas exhibiting inflammation. The results of the present studies suggest that TIMP4 has a special role in the regulation of tissue repair processes in the heart, and also in healing wounds and metastases. Furthermore, evidence is provided suggesting the usefulness of TIMP4 as a novel systemic marker for vascular inflammation.

En generation intellektuella i uppror

Kirjallisuusarvostelu

Legal challenges for next generation science

Presentation at the Nordic Perspectives on Open Access and Open Science seminar, Helsinki, October 15, 2013

Building Next Generation Consortium Services – part 3: The National Metadata Repository, Discovery Service Finna, and the New Library System

Kristiina Hormia-Poutasen esitys CBUC-konferenssissa Barcelonassa 12.4.2013.

Building Next Generation Consortium Services – part 1: Background for Change

Kristiina Hormia-Poutasen esitys CBUC-konferenssissa Barcelonassa 12.4.2013.

Building Next Generation Consortium Services – part 2: Next Generation IT-services – Why, What, When?

Kristiina Hormia-Poutasen esitys CBUC-konferenssissa Barcelonassa 12.4.2013.

Building Next Generation Consortium Services – Introduction to the seminar

Kristiina Hormia-Poutasen esitys CBUC-konferenssissa 12.4.2013 Barcelonassa.

Creating generation Y sources of motivation for enhanced performance

New challenges have been created in the modern work environment as the diversity of the workforce is greater than ever in terms of generations. There will become a large demand of generation Y employees as the baby boomer generation employees retire at an accelerated rate. The purpose of this study is to investigate Y generation specific characteristics and to identify motivational systems to enhance performance. The research questions are: 1. What are Y generation characteristics? 2. What motivational systems organizations can form to motivate Y generation employees and in turn, create better performance? The Y generation specific characteristics identified from the literature include; achievement oriented; confident; educated; multitasking; having a need for feedback; needing management support; sociable and tech savvy. The proposed motivational systems can be found in four areas of the organization; HRM, training and development, communication and decision making policies. Three focus groups were held to investigate what would motivate generation Y employees to achieve better performance. Two of these focus groups were Finnish natives and the third consisted of international students. The HRM systems included flexibility and a culture of fun. It was concluded that flexibility within the workplace and role was a great source of motivation. Culture of fun was not responded to as favorably although most focus group participants rated enjoyableness as one of their top motivating factors. Training and development systems include training programs and mentoring as sources of potential motivation. Training programs were viewed as a mode to gain a better position and were not necessarily seen as motivational systems. Mentoring programs were not concluded to have a significant effect on motivation. Communication systems included keeping up with technology, clarity and goals as well as feedback. Keeping up with technology was seen as an ineffective tool to motivate. Clarity and goal setting was seen as very important to be able to perform but not necessarily motivating. Feedback had a highly motivating effect on these focus groups. Decision making policies included collaboration and teamwork as well as ownership. Teams were familiar and meet the social needs of Y generation employees and are motivating. Ownership was equated with trust and responsibility and was highly valued as well as motivating to these focus group participants.

Bio-ethanol valorization towards C4s including 1-butanol over metal modified alumina and zeolite catalysts

Bio-ethanol has been used as a fuel additive in modern society aimed at reducing CO2-emissions and dependence on oil. However, ethanol is unsuitable as fuel supplement in higher proportions due to its physico-chemical properties. One option to counteract the negative effects is to upgrade ethanol in a continuous fixed bed reactor to more valuable C4 products such as 1-butanol providing chemical similarity with traditional gasoline components. Bio-ethanol based valorization products also have other end-uses than just fuel additives. E.g. 1-butanol and ethyl acetate are well characterised industrial solvents and platform chemicals providing greener alternatives. The modern approach is to apply heterogeneous catalysts in the investigated reactions. The research was concentrated on aluminium oxide (Al2O3) and zeolites that were used as catalysts and catalyst supports. The metals supported (Cu, Ni, Co) gave very different product profiles and, thus, a profound view of different catalyst preparation methods and characterisation techniques was necessary. Additionally, acidity and basicity of the catalyst surface have an important role in determining the product profile. It was observed that ordinary determination of acid strength was not enough to explain all the phenomena e.g. the reaction mechanism. One of the main findings of the thesis is based on the catalytically active site which originates from crystallite structure. As a consequence, the overall evaluation of different by-products and intermediates was carried out by combining the information. Further kinetic analysis was carried out on metal (Cu, Ni, Co) supported self-prepared alumina catalysts. The thesis gives information for further catalyst developments aimed to scale-up towards industrially feasible operations.

Reaching influential early adopters effectively in Finland : Rock Science – new generation board game

Innovations diffuse at different speed among the members of a social system through various communication channels. The group of early adopters can be seen as the most influential reference group for majority of people to base their innovation adoption decisions on. Thus, the early adopters can often accelerate the diffusion of innovations. The purpose of this research is to discover means of diffusion for an innovative product in Finnish market through the influential early adopters in respect to the characteristics of the case product. The purpose of the research can be achieved through the following sub objectives:  Who are the potential early adopters for the case product and why?  How the potential early adopters of the case product should be communicated with?  What would be the expectations, preferences, and experiences of the early adopters of the case product? The case product examined in this research is a new board game called Rock Science which is considered to be incremental innovation bringing board gaming and hard rock music together in a new way. The research was conducted in two different parts using both qualitative and quantitative research methods. This mixed method research began with expert interviews of six music industry experts. The information gathered from the interviews enabled researcher to compose the questionnaire for the quantitative part of the study. Internet survey that was sent out resulted with a sample of 97 responses from the targeted population. The key findings of the study suggest that (1) the potential early adopters for the case product are more likely to be young adults from the capital city area with great interest in rock music, (2) the early adopters can be reached effectively through credible online sources of information, and (3) the respondents overall product feedback is highly positive, except in the case of quality-price ratio of the product. This research indicates that more effective diffusion of Rock Science board game in Finland can be reached through (1) strategic alliances with music industry and media partnerships, (2) pricing adjustments, (3) use of supporting game formats, and (4) innovative use of various social media channels.

Advanced biofuel production: Engineering metabolic pathways for butanol and propane biosynthesis.

Greenhouse gases emitted from energy production and transportation are dramatically changing the climate of Planet Earth. As a consequence, global warming is affecting the living conditions of numerous plant and animal species, including ours. Thus the development of sustainable and renewable liquid fuels is an essential global challenge in order to combat the climate change. In the past decades many technologies have been developed as alternatives to currently used petroleum fuels, such as bioethanol and biodiesel. However, even with gradually increasing production, the market penetration of these first generation biofuels is still relatively small compared to fossil fuels. Researchers have long ago realized that there is a need for advanced biofuels with improved physical and chemical properties compared to bioethanol and with biomass raw materials not competing with food production. Several target molecules have been identified as potential fuel candidates, such as alkanes, fatty acids, long carbon‐chain alcohols and isoprenoids. The current study focuses on the biosynthesis of butanol and propane as possible biofuels. The scope of this research was to investigate novel heterologous metabolic pathways and to identify bottlenecks for alcohol and alkane generation using Escherichia coli as a model host microorganism. The first theme of the work studied the pathways generating butyraldehyde, the common denominator for butanol and propane biosynthesis. Two ways of generating butyraldehyde were described, one via the bacterial fatty acid elongation machinery and the other via partial overexpression of the acetone‐butanol‐ethanol fermentation pathway found in Clostridium acetobutylicum. The second theme of the experimental work studied the reduction of butyraldehyde to butanol catalysed by various bacterial aldehyde‐reductase enzymes, whereas the final part of the work investigated the in vivo kinetics of the cyanobacterial aldehyde deformylating oxygenase (ADO) for the generation of hydrocarbons. The results showed that the novel butanol pathway, based on fatty acid biosynthesis consisting of an acyl‐ACP thioesterase and a carboxylic acid reductase, is tolerant to oxygen, thus being an efficient alternative to the previous Clostridial pathways. It was also shown that butanol can be produced from acetyl‐CoA using acetoacetyl CoA synthase (NphT7) or acetyl‐CoA acetyltransferase (AtoB) enzymes. The study also demonstrated, for the first time, that bacterial biosynthesis of propane is possible. The efficiency of the system is clearly limited by the poor kinetic properties of the ADO enzyme, and for proper function in vivo, the catalytic machinery requires a coupled electron relay system.