Molecular Evolution of Metazoan Hypoxia-inducing Factors

Most metazoans rely on aerobic energy production, which is dependent on adequate oxygen supply. In the case of reduced oxygen supply (hypoxia), the most profound changes in gene expression are mediated by transcription factors named hypoxia-inducible factors (HIF alpha). These proteins are post-translationally regulated by prolyl-4-hydroxylase (PHD) enzymes that are direct “sensors” of cellular oxygen levels. This thesis examines the molecular evolution of metazoan HIF systems. In early metazoans the HIF system emerged from pre-existing PHD oxygen sensors and early bHLH-PAS transcription factors. In invertebrates our analysis revealed an unexpected diversity of PHD genes and HIF alpha sequence characteristics. An early branching vertebrate, the epaulette shark (Hemiscyllium ocellatum) was chosen for sequencing and hypoxia preconditioning studies of HIF alpha and PHD genes. As no quantitative PCR reference genes were available, this thesis includes the first study of reference genes in cartilaginous fish species. Applying multiple statistical analysis we also discoveredthat commonly used reference gene software may perform poorly with some data sets. Novel reference genes allowed accurate measurements of the mRNAlevels of the studied target genes. Cartilaginous fishes have three genomic duplicates of both HIF alpha and PHD genes like mammals and teleost fishes. Combining functional divergence and selection analyses it was possible to describe how sequence changes in both HIF alpha and PHD duplicates may have contributed to the differential oxygen sensitivityof HIF alphas. Additionally, novel teleost HIF-1 alpha sequences were produced and used to reveal the molecular evolution of HIF-1 alpha in this lineage rich with hypoxia tolerant species.

Evolution of Bordetella pertussis post vaccination

Evolution of Bordetella pertussis post vaccination Whooping cough or pertussis is caused by the gram-negative bacterium Bordetella pertussis. It is a highly contiguous disease in the human respiratory tract. Characteristic of pertussis is a paroxysmal cough with whooping sound during gasps of breath after coughing episodes. It is potentially fatal to unvaccinated infants. The best approach to fight pertussis is to vaccinate. Vaccinations against pertussis have been available from the 1940s. Traditionally vaccines were whole-cell pertussis (wP) preparations as part of the combined diphtheria-tetanus-pertussis (DTP) vaccines. More recently acellular pertussis (aP) vaccines have replaced the wP vaccines in many countries. The aP vaccines are less reactogenic and can also be administered to school children and adults. There are several publications reporting variation in the i>B. pertussis virulence factors that are also aP vaccine antigens. This has occurred in the genes coding for pertussis toxin and pertactin about 15 to 30 years after the introduction of pertussis vaccines to immunisation programs. Resurgence of pertussis has also been reported in many countries with high vaccination coverage. In this study the evolution of B. pertussis was investigated in Finland, the United Kingdom, Poland, Serbia, China, Senegal and Kenya. These represent countries with a long history of high vaccination coverage with stable vaccines or changes in the vaccine formulation; countries which established high vaccination coverage late; and countries where vaccinations against pertussis were started late. With bacterial cytotoxicity and cytokine measurements, comparative genomic hybridisation, pulsed-field gel electrophoresis (PFGE), genotyping and serotyping it was found that changes in the vaccine composition can postpone the emergence of antigenic variants. It seems that the change in PFGE profiles and the loss of genetic material in the genome of B. pertussis are similar in most countries and the vaccine-induced immunity is selecting non-vaccine type strains. However, the differences in the formulation of the vaccines, the vaccination programs and in the coverage of pertussis vaccination have affected the speed and timing of these changes.

Convergence in Industry Evolution

The objective of the thesis is to enhance understanding of the evolution of convergence. Previous research has shown that the technological interfaces between distinct industries are one of the major sources of new radical cross-industry innovations. Despite the fact that convergence in industry evolution has attracted a substantial managerial interest, the conceptual confusion within the field of convergence exists. Firstly, this study clarifies the convergence phenomenon and its impact to industry evolution. Secondly, the study creates novel patent analysis methods to analyze technological convergence and provide tools for anticipating the early stages of convergence. Overall the study combines the industry evolution perspective and the convergence view of industrial evolution. The theoretical background for the study consists of the industry life cycle theories, technology evolution, and technological trajectories. The study links several important concepts in analyzing industry evolution, technological discontinuities, path-dependency, technological interfaces as a source of industry transformation, and the evolutionary stagesof convergence. Based on reviewing the literature a generic understanding of industry transformation and industrial dynamics was generated. In the convergence studies, the theoretical basis is in the discussion of different convergence types and their impacts on industry evolution, and in anticipating and monitoring the stages of convergence. The study is divided in two parts. The first part gives a general overview, and the second part comprises eight research publications. Our case study is based historically on two very distinct industries of the paper and electronics companies as a test environment to evaluate the importance of emerging business sectors and technological convergence as a source of industry transformation. Both qualitative and quantitative research methodology are utilized. The results of this study reveal that technological convergence and complementary innovations from different fields have significant effect to the emerging new business sector formation. The patent-based indicators in the analysis of technological convergence can be utilized on analyzing technology competition, capability and competence development, knowledge accumulation, knowledge spill-overs, and technology-based industry transformation. The patent-based indicators can provide insights to the future competitive environment. Results and conclusions from empirical part seem not be in conflict with real observations in the industry.

Generalized Differential Evolution for Global Multi-Objective Optimization with Constraints

The objective of this thesis work is to develop and study the Differential Evolution Algorithm for multi-objective optimization with constraints. Differential Evolution is an evolutionary algorithm that has gained in popularity because of its simplicity and good observed performance. Multi-objective evolutionary algorithms have become popular since they are able to produce a set of compromise solutions during the search process to approximate the Pareto-optimal front. The starting point for this thesis was an idea how Differential Evolution, with simple changes, could be extended for optimization with multiple constraints and objectives. This approach is implemented, experimentally studied, and further developed in the work. Development and study concentrates on the multi-objective optimization aspect. The main outcomes of the work are versions of a method called Generalized Differential Evolution. The versions aim to improve the performance of the method in multi-objective optimization. A diversity preservation technique that is effective and efficient compared to previous diversity preservation techniques is developed. The thesis also studies the influence of control parameters of Differential Evolution in multi-objective optimization. Proposals for initial control parameter value selection are given. Overall, the work contributes to the diversity preservation of solutions in multi-objective optimization.

The Evolution of Securities Lending and Risk Mitigation: A Finnish Market Case Study

Although securities lending is an important function of the financial markets, it has not received that much academic attention. This study examines the evolution of European securities lending and risk management with an emphasis on the development of collateral management, the function responsible for reducing credit risk. The effects of the recent financial instabilities are also considered. The evolution of the Finnish securities lending market is examined in more detail through a case-study. This study can be classified as a constructive qualitative case study. The initial practical knowledge comes from the author's own experience and additional insight and theoretical background is acquired through a literature review. The case study is based on research, semi-structured interviews and a brief analysis of numerical data. The main observation of this study was that securities lending is now recognized as more of an investment management discipline than an operational support function. The recent financial instabilities have resulted in an increased focus on risk and transparency. In securities lending this is directly reflected in collateral management guidelines and procedures. Collateral management has become increasingly technologically developed and automated. Collateral optimization initiatives have been started to make the process more efficient, liquid, and cost effective. Although securities lending is generally an OTC-market with no standard market place, centralized exchange-like models have been introduced. Finnish securities lending has now shifted towards the more common global OTC model. Although the Finnish securities lending industry has developed, and the main laws governing it (tax legislation) have changed, there is still need for development. There are still not many Finnish participants involved and due to legal issues most securities loans are collateralized with cash and not securities (e.g. government bonds).

Differential Evolution approach and parameter estimation of chaotic

Parameter estimation still remains a challenge in many important applications. There is a need to develop methods that utilize achievements in modern computational systems with growing capabilities. Owing to this fact different kinds of Evolutionary Algorithms are becoming an especially perspective field of research. The main aim of this thesis is to explore theoretical aspects of a specific type of Evolutionary Algorithms class, the Differential Evolution (DE) method, and implement this algorithm as codes capable to solve a large range of problems. Matlab, a numerical computing environment provided by MathWorks inc., has been utilized for this purpose. Our implementation empirically demonstrates the benefits of a stochastic optimizers with respect to deterministic optimizers in case of stochastic and chaotic problems. Furthermore, the advanced features of Differential Evolution are discussed as well as taken into account in the Matlab realization. Test "toycase" examples are presented in order to show advantages and disadvantages caused by additional aspects involved in extensions of the basic algorithm. Another aim of this paper is to apply the DE approach to the parameter estimation problem of the system exhibiting chaotic behavior, where the well-known Lorenz system with specific set of parameter values is taken as an example. Finally, the DE approach for estimation of chaotic dynamics is compared to the Ensemble prediction and parameter estimation system (EPPES) approach which was recently proposed as a possible solution for similar problems.

Model-View-Controller architectural pattern and its evolution in graphical user interface frameworks

Model-View-Controller (MVC) is an architectural pattern used in software development for graphical user interfaces. It was one of the first proposed solutions in the late 1970s to the Smart UI anti-pattern, which refers to the act of writing all domain logic into a user interface. The original MVC pattern has since evolved in multiple directions, with various names and may confuse many. The goal of this thesis is to present the origin of the MVC pattern and how it has changed over time. Software architecture in general and the MVC’s evolution within web applications are not the primary focus. Fundamen- tal designs are abstracted, and then used to examine the more recent versions. Prob- lems with the subject and its terminology are also presented.

Methods of genetic diversity creation and functional display for directed evolution experiments

Protein engineering aims to improve the properties of enzymes and affinity reagents by genetic changes. Typical engineered properties are affinity, specificity, stability, expression, and solubility. Because proteins are complex biomolecules, the effects of specific genetic changes are seldom predictable. Consequently, a popular strategy in protein engineering is to create a library of genetic variants of the target molecule, and render the population in a selection process to sort the variants by the desired property. This technique, called directed evolution, is a central tool for trimming protein-based products used in a wide range of applications from laundry detergents to anti-cancer drugs. New methods are continuously needed to generate larger gene repertoires and compatible selection platforms to shorten the development timeline for new biochemicals. In the first study of this thesis, primer extension mutagenesis was revisited to establish higher quality gene variant libraries in Escherichia coli cells. In the second study, recombination was explored as a method to expand the number of screenable enzyme variants. A selection platform was developed to improve antigen binding fragment (Fab) display on filamentous phages in the third article and, in the fourth study, novel design concepts were tested by two differentially randomized recombinant antibody libraries. Finally, in the last study, the performance of the same antibody repertoire was compared in phage display selections as a genetic fusion to different phage capsid proteins and in different antibody formats, Fab vs. single chain variable fragment (ScFv), in order to find out the most suitable display platform for the library at hand. As a result of the studies, a novel gene library construction method, termed selective rolling circle amplification (sRCA), was developed. The method increases mutagenesis frequency close to 100% in the final library and the number of transformants over 100-fold compared to traditional primer extension mutagenesis. In the second study, Cre/loxP recombination was found to be an appropriate tool to resolve the DNA concatemer resulting from error-prone RCA (epRCA) mutagenesis into monomeric circular DNA units for higher efficiency transformation into E. coli. Library selections against antigens of various size in the fourth study demonstrated that diversity placed closer to the antigen binding site of antibodies supports generation of antibodies against haptens and peptides, whereas diversity at more peripheral locations is better suited for targeting proteins. The conclusion from a comparison of the display formats was that truncated capsid protein three (p3Δ) of filamentous phage was superior to the full-length p3 and protein nine (p9) in obtaining a high number of uniquely specific clones. Especially for digoxigenin, a difficult hapten target, the antibody repertoire as ScFv-p3Δ provided the clones with the highest affinity for binding. This thesis on the construction, design, and selection of gene variant libraries contributes to the practical know-how in directed evolution and contains useful information for scientists in the field to support their undertakings.

AgEcon Search: Evolution of a Subject Repository

Poster at Open Repositories 2014, Helsinki, Finland, June 9-13, 2014

Evolver: The Evolution of The Extended EPrints Ecosystem

Presentation at Open Repositories 2014, Helsinki, Finland, June 9-13, 2014

Genesis and Evolution of Brittle Structures In Southwestern Finland and Western South Africa. Insights into Fault Reactivation, Fluid Flow and Structural Maturity in Precambrian Cratons

The bedrock of old crystalline cratons is characteristically saturated with brittle structures formed during successive superimposed episodes of deformation and under varying stress regimes. As a result, the crust effectively deforms through the reactivation of pre-existing structures rather than by through the activation, or generation, of new ones, and is said to be in a state of 'structural maturity'. By combining data from Olkiluoto Island, southwestern Finland, which has been investigated as the potential site of a deep geological repository for high-level nuclear waste, with observations from southern Sweden, it can be concluded that the southern part of the Svecofennian shield had already attained structural maturity during the Mesoproterozoic era. This indicates that the phase of activation of the crust, i.e. the time interval during which new fractures were generated, was brief in comparison to the subsequent reactivation phase. Structural maturity of the bedrock was also attained relatively rapidly in Namaqualand, western South Africa, after the formation of first brittle structures during Neoproterozoic time. Subsequent brittle deformation in Namaqualand was controlled by the reactivation of pre-existing strike-slip faults.In such settings, seismic events are likely to occur through reactivation of pre-existing zones that are favourably oriented with respect to prevailing stresses. In Namaqualand, this is shown for present day seismicity by slip tendency analysis, and at Olkiluoto, for a Neoproterozoic earthquake reactivating a Mesoproterozoic fault. By combining detailed field observations with the results of paleostress inversions and relative and absolute time constraints, seven distinctm superimposed paleostress regimes have been recognized in the Olkiluoto region. From oldest to youngest these are: (1) NW-SE to NNW-SSE transpression, which prevailed soon after 1.75 Ga, when the crust had sufficiently cooled down to allow brittle deformation to occur. During this phase conjugate NNW-SSE and NE-SW striking strike-slip faults were active simultaneous with reactivation of SE-dipping low-angle shear zones and foliation planes. This was followed by (2) N-S to NE-SW transpression, which caused partial reactivation of structures formed in the first event; (3) NW-SE extension during the Gothian orogeny and at the time of rapakivi magmatism and intrusion of diabase dikes; (4) NE-SW transtension that occurred between 1.60 and 1.30 Ga and which also formed the NW-SE-trending Satakunta graben located some 20 km north of Olkiluoto. Greisen-type veins also formed during this phase. (5) NE-SW compression that postdates both the formation of the 1.56 Ga rapakivi granites and 1.27 Ga olivine diabases of the region; (6) E-W transpression during the early stages of the Mesoproterozoic Sveconorwegian orogeny and which also predated (7) almost coaxial E-W extension attributed to the collapse of the Sveconorwegian orogeny. The kinematic analysis of fracture systems in crystalline bedrock also provides a robust framework for evaluating fluid-rock interaction in the brittle regime; this is essential in assessment of bedrock integrity for numerous geo-engineering applications, including groundwater management, transient or permanent CO2 storage and site investigations for permanent waste disposal. Investigations at Olkiluoto revealed that fluid flow along fractures is coupled with low normal tractions due to in-situ stresses and thus deviates from the generally accepted critically stressed fracture concept, where fluid flow is concentrated on fractures on the verge of failure. The difference is linked to the shallow conditions of Olkiluoto - due to the low differential stresses inherent at shallow depths, fracture activation and fluid flow is controlled by dilation due to low normal tractions. At deeper settings, however, fluid flow is controlled by fracture criticality caused by large differential stress, which drives shear deformation instead of dilation.

Differential evolution based classification with pool of distances and aggregation operators

The objective of this thesis is to develop and generalize further the differential evolution based data classification method. For many years, evolutionary algorithms have been successfully applied to many classification tasks. Evolution algorithms are population based, stochastic search algorithms that mimic natural selection and genetics. Differential evolution is an evolutionary algorithm that has gained popularity because of its simplicity and good observed performance. In this thesis a differential evolution classifier with pool of distances is proposed, demonstrated and initially evaluated. The differential evolution classifier is a nearest prototype vector based classifier that applies a global optimization algorithm, differential evolution, to determine the optimal values for all free parameters of the classifier model during the training phase of the classifier. The differential evolution classifier applies the individually optimized distance measure for each new data set to be classified is generalized to cover a pool of distances. Instead of optimizing a single distance measure for the given data set, the selection of the optimal distance measure from a predefined pool of alternative measures is attempted systematically and automatically. Furthermore, instead of only selecting the optimal distance measure from a set of alternatives, an attempt is made to optimize the values of the possible control parameters related with the selected distance measure. Specifically, a pool of alternative distance measures is first created and then the differential evolution algorithm is applied to select the optimal distance measure that yields the highest classification accuracy with the current data. After determining the optimal distance measures for the given data set together with their optimal parameters, all determined distance measures are aggregated to form a single total distance measure. The total distance measure is applied to the final classification decisions. The actual classification process is still based on the nearest prototype vector principle; a sample belongs to the class represented by the nearest prototype vector when measured with the optimized total distance measure. During the training process the differential evolution algorithm determines the optimal class vectors, selects optimal distance metrics, and determines the optimal values for the free parameters of each selected distance measure. The results obtained with the above method confirm that the choice of distance measure is one of the most crucial factors for obtaining higher classification accuracy. The results also demonstrate that it is possible to build a classifier that is able to select the optimal distance measure for the given data set automatically and systematically. After finding optimal distance measures together with optimal parameters from the particular distance measure results are then aggregated to form a total distance, which will be used to form the deviation between the class vectors and samples and thus classify the samples. This thesis also discusses two types of aggregation operators, namely, ordered weighted averaging (OWA) based multi-distances and generalized ordered weighted averaging (GOWA). These aggregation operators were applied in this work to the aggregation of the normalized distance values. The results demonstrate that a proper combination of aggregation operator and weight generation scheme play an important role in obtaining good classification accuracy. The main outcomes of the work are the six new generalized versions of previous method called differential evolution classifier. All these DE classifier demonstrated good results in the classification tasks.