Methods for construction and analysis of computational models in systems biology : applications to the modelling of the heat shock response and the self-assembly of intermediate filaments

Systems biology is a new, emerging and rapidly developing, multidisciplinary research field that aims to study biochemical and biological systems from a holistic perspective, with the goal of providing a comprehensive, system- level understanding of cellular behaviour. In this way, it addresses one of the greatest challenges faced by contemporary biology, which is to compre- hend the function of complex biological systems. Systems biology combines various methods that originate from scientific disciplines such as molecu- lar biology, chemistry, engineering sciences, mathematics, computer science and systems theory. Systems biology, unlike “traditional” biology, focuses on high-level concepts such as: network, component, robustness, efficiency, control, regulation, hierarchical design, synchronization, concurrency, and many others. The very terminology of systems biology is “foreign” to “tra- ditional” biology, marks its drastic shift in the research paradigm and it indicates close linkage of systems biology to computer science. One of the basic tools utilized in systems biology is the mathematical modelling of life processes tightly linked to experimental practice. The stud- ies contained in this thesis revolve around a number of challenges commonly encountered in the computational modelling in systems biology. The re- search comprises of the development and application of a broad range of methods originating in the fields of computer science and mathematics for construction and analysis of computational models in systems biology. In particular, the performed research is setup in the context of two biolog- ical phenomena chosen as modelling case studies: 1) the eukaryotic heat shock response and 2) the in vitro self-assembly of intermediate filaments, one of the main constituents of the cytoskeleton. The range of presented approaches spans from heuristic, through numerical and statistical to ana- lytical methods applied in the effort to formally describe and analyse the two biological processes. We notice however, that although applied to cer- tain case studies, the presented methods are not limited to them and can be utilized in the analysis of other biological mechanisms as well as com- plex systems in general. The full range of developed and applied modelling techniques as well as model analysis methodologies constitutes a rich mod- elling framework. Moreover, the presentation of the developed methods, their application to the two case studies and the discussions concerning their potentials and limitations point to the difficulties and challenges one encounters in computational modelling of biological systems. The problems of model identifiability, model comparison, model refinement, model inte- gration and extension, choice of the proper modelling framework and level of abstraction, or the choice of the proper scope of the model run through this thesis.

Key factors in transforming university internationalization into commercial activity in Finland. Case of University of Turku

Globalization, developments in ICT, emergence of knowledge society and other changes have reformed the environment for international higher education during the past few decades. Consequently, higher education sector has moved towards more marketing-oriented system, and universities have started to undertake commercial activities as part of their internationalization. This development has emerged to Finland as well, which forms the basis for this study. The purpose is to examine commercialization in Finnish university landscape and to investigate the ways Finnish university could capitalize its international activities and educational knowledge for export. The research question of the study is: What are the key factors in transforming university internationalization into commercial activity in the Finnish university landscape? The main problem is further divided into three sub-questions: 1) How can a university internationalize; 2) what are the motivational factors behind university internationalization and commercialization; and 3) how can higher education be developed into export services and products? The research was conducted as a qualitative case study of University of Turku. Methods used for gathering and examining data were interviewing and document analysis. Primary data was collected through four individual semi-structured interviews, which were conducted face-to-face. Secondary data that included reports, articles and electronic materials such as university web pages, was used to complement the primary data. The results were analyzed by theming the data into three broader categories of internationalization activities; drivers and motivations and; education export activities. After the data was organized in themes, analysis continued by comparing different parts of data and finding patterns that would explain the phenomenon in Finnish universities. According to the empirical data, University of Turku is currently on the growth state of internationalization with strategies such as internationalization of curriculum, establishment of international research groups, mobility of students and academics, international networking and support services. Commercialization phenomenon is still rather new to the case university, but it has already developed educational products and services for export. The study concludes that university internationalization cannot be directly transformed into commercial activities in the Finnish context, but the universities need to be active in actually creating educational products. The key factors found in this study include: 1) the Finnish government policies behind the current hype of export education; 2) the potential and knowledge capacity of universities for exports; 3) need for additional profits; 4) further internationalization through commercial activities; 5) recognizing and exploiting the specific areas of strength and 6) establishing of cooperative partnerships for better products.

Control of the phosphorylation of the astrocyte marker glial fibrillary acidic protein (GFAP) in the immature rat hippocampus by glutamate and calcium ions: possible key factor in astrocytic plasticity

The present review describes recent research on the regulation by glutamate and Ca2+ of the phosphorylation state of the intermediate filament protein of the astrocytic cytoskeleton, glial fibrillary acidic protein (GFAP), in immature hippocampal slices. The results of this research are discussed against a background of modern knowledge of the functional importance of astrocytes in the brain and of the structure and dynamic properties of intermediate filament proteins. Astrocytes are now recognized as partners with neurons in many aspects of brain function with important roles in neural plasticity. Site-specific phosphorylation of intermediate filament proteins, including GFAP, has been shown to regulate the dynamic equilibrium between the polymerized and depolymerized state of the filaments and to play a fundamental role in mitosis. Glutamate was found to increase the phosphorylation state of GFAP in hippocampal slices from rats in the post-natal age range of 12-16 days in a reaction that was dependent on external Ca2+. The lack of external Ca2+ in the absence of glutamate also increased GFAP phosphorylation to the same extent. These effects of glutamate and Ca2+ were absent in adult hippocampal slices, where the phosphorylation of GFAP was completely Ca2+-dependent. Studies using specific agonists of glutamate receptors showed that the glutamate response was mediated by a G protein-linked group II metabotropic glutamate receptor (mGluR). Since group II mGluRs do not act by liberating Ca2+ from internal stores, it is proposed that activation of the receptor by glutamate inhibits Ca2+ entry into the astrocytes and consequently down-regulates a Ca2+-dependent dephosphorylation cascade regulating the phosphorylation state of GFAP. The functional significance of these results may be related to the narrow developmental window when the glutamate response is present. In the rat brain this window corresponds to the period of massive synaptogenesis during which astrocytes are known to proliferate. Possibly, glutamate liberated from developing synapses during this period may signal an increase in the phosphorylation

Interferon gamma is a key cytokine in lung phase immunity to schistosomes but what is its precise role?

Vaccination of mice with radiation-attenuated cercariae of Schistosoma mansoni induces a high level of protection against challenge with normal larvae. The immune effector mechanism, which operates in the lungs, is a cell-mediated delayed-type hypersensitivity response and involves the formation of a tight focus of mononuclear cells around embolised larvae. CD4+ T cells with Th1 characteristics are a major component of the infiltrate. They secrete abundant interferon gamma (IFNg) upon antigen stimulation in vitro, whilst in vivo neutralisation of the cytokine results in 90% abrogation of immunity. IFNg can induce a large number of genes and an attempt has been made to identify the ones which are essential components of the effector mechanism. Inducible nitric oxide synthase (iNOS) is such a candidate and nitric oxide (NO) is produced by cultures of airway leucocytes from the lungs of vaccinated mice post-challenge. However, the continued resistance of mice with a disrupted iNOS gene indicates that NO has only a minor role in the protective response. Mice with a disrupted IFNg receptor gene have been used to dissect the role of the cytokine. After vaccination and challenge, CD4+ T cells from the pulmonary interstitium have reduced levels of ICAM-1 and LFA-1 expression, compared to wild-type animals, which coincides with a reduced cohesiveness of foci. However, immunity is not significantly impaired in mice with a disrupted ICAM-1 gene, and focus formation is normal. Similarly, a role has not been found for CD2/CD48 interactions in cell aggregation. Possible IFNg-inducible molecules yet to be fully investigated include other ligand-receptor pairs, chemokines, and tumour necrosis factor a.

Key factors in U.S. Government support of business internationalization in Finland Case: U.S. Embassy in Helsinki

This study discusses the importance of government intervention for companies and the expansion of national innovation systems. The purpose of the study is to examine the impact which the U.S. Embassy in Helsinki can have on Finnish businesses through their business support programs and events. The embassy has shifted focus in recent years with the creation of an innovation center and increased business services. The study has sub-objectives to discover the critical factors for producing impact, host and home based factor interaction, and effects produced by these initiatives. The theoretical background of the study consists of literature relating to the concepts of national innovation systems and government intervention. The empirical research conduct for this study is based on interviews with experts from the environment surrounding the U.S. Embassy in Helsinki, Finland and participation in embassy events. The data was collected between March 2014 and September 2015. Seven interviews were conducted; five with representatives of the U.S. Embassy and two with related organizations. Thematic analysis was used to categorize and interpret interview and observation data. The use of an impact radar was implemented as a basis for analysis. This study finds that the internationalization of national innovation systems provides interesting opportunities and challenges for national governments. The opportunity to provide services to foreign companies by an embassy in a stable environment opens the possibility to create positive notice and relations with the host country. The increased connections and inputs to the national innovation system of the home country have the potential to increase knowledge absorption and create positive growth. The most effective way for governments to encourage businesses is to create incentives and reduce barriers. The services are best aimed at small to medium sized companies in the early stages of development. The findings of this report suggest that the most critical factors for producing impact on companies are the ability to disseminate information effectively, the ability to create a positive image of the country, the ability to foster effective networks between the two countries, and the ability to facilitate the internationalization of companies. In the best cases, the embassy is able to create incentives to internationalize to the United States and reduce barriers which are encountered by companies. Future research is necessary to fully understand the impact of business services provided by an embassy can have on the political and economic relations of countries, and on particular industry sectors. The institutional setting provided by the embassy’s focus on business relations provides a rich environment for further study in a number of areas.

Selected topics in fast atom bombardment (FAB) mass spectrometry a)specially designed probe tips and ion generation, b)structures of vitamin B6 schiff base complexes

This thesis can be broken down into two sections. Section one is a study . of the ionization mechanisms and the ion source optimization for Fast Atom Bombardment (FAB) ionization. For this study, several specially designed probe tips were created and tested under various experimental conditions. The aIm of this section is to understand the operating characteristics of a FAB IOn source better. The second section involves the study of several Vitamin B6 Schiff Base complexes using both positive and negative ion FAB MS. This section is an exploration of the usefulness of FAB MS as a structure probe for the metalcoordination complexes of Vitamin B6.

Metaphorical Conceptualization in Cell Biology

Département de linguistique et de traduction

Assessment of PEG on Polymeric Particles Surface, a Key Step in Drug Carrier Translation

Injectable drug nanocarriers have greatly benefited in their clinical development from the addition of a superficial hydrophilic corona to improve their cargo pharmacokinetics. The most studied and used polymer for this purpose is poly(ethylene glycol), PEG. However, in spite of its wide use for over two decades now, there is no general consensus on the optimum PEG chain coverage-density and size required to escape from the mononuclear phagocyte system and to extend the circulation time. Moreover, cellular uptake and active targeting may have conflicting requirements in terms of surface properties of the nanocarriers which complicates even more the optimization process. These persistent issues can be largely attributed to the lack of straightforward characterization techniques to assess the coverage-density, the conformation or the thickness of a PEG layer grafted or adsorbed on a particulate drug carrier and is certainly one of the main reasons why so few clinical applications involving PEG coated particle-based drug delivery systems are under clinical trial so far. The objective of this review is to provide the reader with a brief description of the most relevant techniques used to assess qualitatively or quantitatively PEG chain coverage-density, conformation and layer thickness on polymeric nanoparticles. Emphasis has been made on polymeric particle (solid core) either made of copolymers containing PEG chains or modified after particle formation. Advantages and limitations of each technique are presented as well as methods to calculate PEG coverage-density and to investigate PEG chains conformation on the NP surface.

‘Studies on some topics in product graphs’

For routing problems in interconnection networks it is important to find the shortest containers between any two vertices, since the w-wide diameter gives the maximum communication delay when there are up to w−1 faulty nodes in a network modeled by a graph. The concept of ‘wide diameter’ was introduced by Hsu [41] to unify the concepts of diameter and The concept of ‘domination’ has attracted interest due to its wide applications in many real world situations [38]. A connected dominating set serves as a virtual backbone of a network and it is a set of vertices that helps in routing. In this thesis, we make an earnest attempt to study some of these notions in graph products. This include, the diameter variability, the diameter vulnerability, the component factors and the domination criticality.connectivity

Matrix based Key Generation to Enhance Key Avalanche in Advanced Encryption Standard

In symmetric block ciphers, substitution and diffusion operations are performed in multiple rounds using sub-keys generated from a key generation procedure called key schedule. The key schedule plays a very important role in deciding the security of block ciphers. In this paper we propose a complex key generation procedure, based on matrix manipulations, which could be introduced in symmetric ciphers. The proposed key generation procedure offers two advantages. First, the procedure is simple to implement and has complexity in determining the sub-keys through crypt analysis. Secondly, the procedure produces a strong avalanche effect making many bits in the output block of a cipher to undergo changes with one bit change in the secret key. As a case study, matrix based key generation procedure has been introduced in Advanced Encryption Standard (AES) by replacing the existing key schedule of AES. The key avalanche and differential key propagation produced in AES have been observed. The paper describes the matrix based key generation procedure and the enhanced key avalanche and differential key propagation produced in AES. It has been shown that, the key avalanche effect and differential key propagation characteristics of AES have improved by replacing the AES key schedule with the Matrix based key generation procedure