The challenge of vector development in gene therapy

Gene therapy is the treatment of diseases based on the transfer of genetic information. Agents that carry or deliver DNA to target cells are called vectors (Latin vector: carrier, deliverer). Ideally, a vector should accommodate an unlimited amount of inserted DNA, lack the ability of autonomous replication of its own DNA, be easily manufactured, and be available in concentrated form. Secondly, it should have the ability to target specific cell types or to limit its gene expression to specific cell types, and to achieve sustained gene expression in the long term or in a controlled fashion. Finally, it should not be toxic or immunogenic. Such a vector does not exist and none of the DNA delivery systems so far available for in vivo gene transfer is perfect with respect to any of these points. Gene therapy and the means to promote it depend heavily on the development and improvement of new gene vector systems.

Novel genes and regulatory systems in epididymal differentiation and sperm maturation of the mouse.

Mammalian spermatozoa gain their fertilizing ability during maturation in the epididymis. Proteins and lipids secreted into the epididymal lumen remodel the sperm membrane, thereby providing the structure necessary for progressive motility and oocyte interaction. In the current study, genetically modified mouse models were utilized to determine the role of novel genes and regulatory systems in the postnatal development and function of the epididymis. Ablation of the mouse β-defensin, Defb41, altered the flagellar movements of sperm and reduced the ability of sperm to bind to the oocyte in vitro. The Defb41-deficient iCre knock-in mouse model was furthermore utilized to generate Dicer1 conditional knock-out (cKO) mice. DICER1 is required for production of mature microRNAs in the regulation of gene expression by RNA interference. Dicer1 cKO gave rise to dedifferentiation of the epididymal epithelium and an altered expression of genes involved in lipid synthesis. As a consequence, the cholesterol:polyunsaturated fatty acid ratio of the Dicer1 cKO sperm membrane was increased, which resulted in membrane instability and infertility. In conclusion, the results of the Defb41 study further support the important role of β-defensin family members in sperm maturation. The regulatory role of Dicer1 was also shown to be required for epididymal development. In addition, the study is the first to show a clear connection between lipid homeostasis in the epididymis and sperm membrane integrity. Taken together, the results give important new evidence on the regulatory system guiding epididymal development and function

Decision making and decision support in service systems

This thesis is a literature study that develops a conceptual model of decision making and decision support in service systems. The study is related to the Ä-Logi, Intelligent Service Logic for Welfare Sector Services research project, and the objective of the study is to develop the necessary theoretical framework to enable further research based on the research project results and material. The study first examines the concepts of service and service systems, focusing on understanding the characteristics of service systems and their implications for decision making and decision support to provide the basis for the development of the conceptual model. Based on the identified service system characteristics, an integrated model of service systems is proposed that views service systems through a number of interrelated perspectives that each offer different, but complementary, implications on the nature of decision making and the requirements for decision support in service systems. Based on the model, it is proposed that different types of decision making contexts can be identified in service systems that may be dominated by different types of decision making processes and where different types of decision support may be required, depending on the characteristics of the decision making context and its decision making processes. The proposed conceptual model of decision making and decision support in service systems examines the characteristics of decision making contexts and processes in service systems, and their typical requirements for decision support. First, a characterization of different types of decision making contexts in service systems is proposed based on the Cynefin framework and the identified service system characteristics. Second, the nature of decision making processes in service systems is proposed to be dual, with both rational and naturalistic decision making processes existing in service systems, and having an important and complementary role in decision making in service systems. Finally, a characterization of typical requirements for decision support in service systems is proposed that examines the decision support requirements associated with different types of decision making processes in characteristically different types of decision making contexts. It is proposed that decision support for the decision making processes that are based on rational decision making can be based on organizational decision support models, while decision support for the decision making processes that are based on naturalistic decision making should be based on supporting the decision makers’ situation awareness and facilitating the development of their tacit knowledge of the system and its tasks. Based on the proposed conceptual model a further research process is proposed. The study additionally provides a number of new perspectives on the characteristics of service systems, and the nature of decision making and requirements for decision support in service systems that can potentially provide a basis for further discussion and research, and support the practice alike.

The use of protein structure/activity relationships in the rational design of stable particulate delivery systems

The recombinant heat shock protein (18 kDa-hsp) from Mycobacterium leprae was studied as a T-epitope model for vaccine development. We present a structural analysis of the stability of recombinant 18 kDa-hsp during different processing steps. Circular dichroism and ELISA were used to monitor protein structure after thermal stress, lyophilization and chemical modification. We observed that the 18 kDa-hsp is extremely resistant to a wide range of temperatures (60% of activity is retained at 80ºC for 20 min). N-Acylation increased its ordered structure by 4% and decreased its ß-T1 structure by 2%. ELISA demonstrated that the native conformation of the 18 kDa-hsp was preserved after hydrophobic modification by acylation. The recombinant 18 kDa-hsp resists to a wide range of temperatures and chemical modifications without loss of its main characteristic, which is to be a source of T epitopes. This resistance is probably directly related to its lack of organization at the level of tertiary and secondary structures.

Comparison of Different Concentrated Solar Power Collector Designs and Development of a Linear Fresnel Solar Collector Model

Concentrated solar power (CSP) is a renewable energy technology, which could contribute to overcoming global problems related to pollution emissions and increasing energy demand. CSP utilizes solar irradiation, which is a variable source of energy. In order to utilize CSP technology in energy production and reliably operate a solar field including thermal energy storage system, dynamic simulation tools are needed in order to study the dynamics of the solar field, to optimize production and develop control systems. The object of this Master’s Thesis is to compare different concentrated solar power technologies and configure a dynamic solar field model of one selected CSP field design in the dynamic simulation program Apros, owned by VTT and Fortum. The configured model is based on German Novatec Solar’s linear Fresnel reflector design. Solar collector components including dimensions and performance calculation were developed, as well as a simple solar field control system. The preliminary simulation results of two simulation cases under clear sky conditions were good; the desired and stable superheated steam conditions were maintained in both cases, while, as expected, the amount of steam produced was reduced in the case having lower irradiation conditions. As a result of the model development process, it can be concluded, that the configured model is working successfully and that Apros is a very capable and flexible tool for configuring new solar field models and control systems and simulating solar field dynamic behaviour.

Development of Generic Simulation Model for Mobile Working Machines

This master’s thesis has been done for Drive! –project in which a new electric motor solution for mobile working machines is developed. Generic simulation model will be used as marketing and development tool. It can be used to model a wide variety of different vehicles with and without electric motor and to show customer the difference between traditionally build vehicles and those with new electric motor solution. Customers can also use simulation model to research different solutions for their own vehicles. At the start of the project it was decided that MeVEA software would be used as main simulation program and Simulink will only be used to simulate the operation of electrical components. Development of the generic model started with the research of these two software applications, simulation models which are made with them and how these simulation models can be build faster. Best results were used for building of generic simulation model. Finished generic model can be used to produce new tractor models for real-time simulations in short notice. All information about model is collected to one datasheet which can be easily filled by the user. After datasheet is filled a script will automatically build new simulation model in seconds. At the moment generic model is capable of building simulation models for wide variety of different tractors but it can be easily altered for other vehicle types too which would also benefit greatly from electric drive solution. Those could be for example wheel loaders and harvesters.

Supply base development for life-cycle business

Yritysten liiketoimintamallit ovat jatkuvan kehityksen kohteena. Viimeisinä vuosina valmistavien yhtiöiden kiinnostus huolehtia asiakkaistaan koko tuotteen elinkaaren aikana ja tarjota erilaisia palveluita asiakkailleen on kasvanut. Tämän palvelujen laajentumisen myötä myös vaateet yrityksen omaa toimittajakenttää kohtaan ovat muuttuneet. Yritykset eivät kykene tuottamaan kaikkia tuotteistamiaan palveluja itse, jolloin yrityksen toimittajakenttä ja sen kyvykkyydet tuottaa tarvittavia palveluita ovat avainasemassa yrityksen menestystekijänä. Tämän työn teoriaosuudessa on esitelty toimittajakentän hallinnan perusteorioita. Kirjallisuus osuuden lisäksi työssä on hyödynnetty toimintatutkimusta kohdeyrityksessä. Tässä diplomityössä on tutkittu mahdollisia keinoja kehittää organisaation omaa toimintaa ja sekä yrityksen toimittajakenttää niin, että se tukee liiketoimintamallin kehitystä koneenrakennusyrityksestä kohti elinkaariliiketoimintaa. Työssä esitetyt keinot voidaan ottaa käyttöön, joko yksitellen tai kokonaisuutena.

Development of project cash flow forecasting process

Process management refers to improving the key functions of a company. The main functions of the case company - project management, procurement, finance, and human resource - use their own separate systems. The case company is in the process of changing its software. Different functions will use the same system in the future. This software change causes changes in some of the company’s processes. Project cash flow forecasting process is one of the changing processes. Cash flow forecasting ensures the sufficiency of money and prepares for possible changes in the future. This will help to ensure the company’s viability. The purpose of the research is to describe a new project cash flow forecasting process. In addition, the aim is to analyze the impacts of the process change, with regard to the project control department’s workload and resources through the process measurement, and how the impacts take the department’s future operations into account. The research is based on process management. Processes, their descriptions, and the way the process management uses the information, are discussed in the theory part of this research. The theory part is based on literature and articles. Project cash flow and forecasting-related benefits are also discussed. After this, the project cash flow forecasting as-is and to-be processes are described by utilizing information, obtained from the theoretical part, as well as the know-how of the project control department’s personnel. Written descriptions and cross-functional flowcharts are used for descriptions. Process measurement is based on interviews with the personnel – mainly cost controllers and department managers. The process change and the integration of two processes will allow work time for other things, for example, analysis of costs. In addition to the quality of the cash flow information will improve compared to the as-is process. Analyzing the department’s other main processes, department’s roles, and their responsibilities should be checked and redesigned. This way, there will be an opportunity to achieve the best possible efficiency and cost savings.

Development of fetal nicotine and muscarinic receptors in utero

The role of acetylcholine in the central and peripheral nervous systems is well established in adults. Cholinergic modulation of vascular functions and body fluid balance has been extensively studied. In the embryo-fetus, cholinergic receptors are widespread in the peripheral and central systems, including smooth muscle and the epithelial lining of the cardiovascular, digestive, and urinary systems, as well as in the brain. Fetal nicotine and muscarinic receptors develop in a pattern (e.g., amount and distribution) related to gestational periods. Cholinergic mechanisms have been found to be relatively intact and functional in the control of vascular homeostasis during fetal life in utero at least during the last third of gestation. This review focuses on the development of fetal nicotine and muscarinic receptors, and provides information indicating that central cholinergic systems are well developed in the control of fetal blood pressure and body fluid balance before birth. Therefore, the development of cholinergic systems in utero plays an important role in fetal vascular regulation, gastrointestinal motility, and urinary control.

Recombinant vaccines and the development of new vaccine strategies

Vaccines were initially developed on an empirical basis, relying mostly on attenuation or inactivation of pathogens. Advances in immunology, molecular biology, biochemistry, genomics, and proteomics have added new perspectives to the vaccinology field. The use of recombinant proteins allows the targeting of immune responses focused against few protective antigens. There are a variety of expression systems with different advantages, allowing the production of large quantities of proteins depending on the required characteristics. Live recombinant bacteria or viral vectors effectively stimulate the immune system as in natural infections and have intrinsic adjuvant properties. DNA vaccines, which consist of non-replicating plasmids, can induce strong long-term cellular immune responses. Prime-boost strategies combine different antigen delivery systems to broaden the immune response. In general, all of these strategies have shown advantages and disadvantages, and their use will depend on the knowledge of the mechanisms of infection of the target pathogen and of the immune response required for protection. In this review, we discuss some of the major breakthroughs that have been achieved using recombinant vaccine technologies, as well as new approaches and strategies for vaccine development, including potential shortcomings and risks.

Model-based testing of software systems : functionality and performance

Software is a key component in many of our devices and products that we use every day. Most customers demand not only that their devices should function as expected but also that the software should be of high quality, reliable, fault tolerant, efficient, etc. In short, it is not enough that a calculator gives the correct result of a calculation, we want the result instantly, in the right form, with minimal use of battery, etc. One of the key aspects for succeeding in today's industry is delivering high quality. In most software development projects, high-quality software is achieved by rigorous testing and good quality assurance practices. However, today, customers are asking for these high quality software products at an ever-increasing pace. This leaves the companies with less time for development. Software testing is an expensive activity, because it requires much manual work. Testing, debugging, and verification are estimated to consume 50 to 75 per cent of the total development cost of complex software projects. Further, the most expensive software defects are those which have to be fixed after the product is released. One of the main challenges in software development is reducing the associated cost and time of software testing without sacrificing the quality of the developed software. It is often not enough to only demonstrate that a piece of software is functioning correctly. Usually, many other aspects of the software, such as performance, security, scalability, usability, etc., need also to be verified. Testing these aspects of the software is traditionally referred to as nonfunctional testing. One of the major challenges with non-functional testing is that it is usually carried out at the end of the software development process when most of the functionality is implemented. This is due to the fact that non-functional aspects, such as performance or security, apply to the software as a whole. In this thesis, we study the use of model-based testing. We present approaches to automatically generate tests from behavioral models for solving some of these challenges. We show that model-based testing is not only applicable to functional testing but also to non-functional testing. In its simplest form, performance testing is performed by executing multiple test sequences at once while observing the software in terms of responsiveness and stability, rather than the output. The main contribution of the thesis is a coherent model-based testing approach for testing functional and performance related issues in software systems. We show how we go from system models, expressed in the Unified Modeling Language, to test cases and back to models again. The system requirements are traced throughout the entire testing process. Requirements traceability facilitates finding faults in the design and implementation of the software. In the research field of model-based testing, many new proposed approaches suffer from poor or the lack of tool support. Therefore, the second contribution of this thesis is proper tool support for the proposed approach that is integrated with leading industry tools. We o er independent tools, tools that are integrated with other industry leading tools, and complete tool-chains when necessary. Many model-based testing approaches proposed by the research community suffer from poor empirical validation in an industrial context. In order to demonstrate the applicability of our proposed approach, we apply our research to several systems, including industrial ones.

Sustainable Development – the Key to Competitiveness CSR as an added value to Alstom’s corporate performance

Corporate social responsibility or CSR is today a widely recognized concept which is receiving in- creasing popularity extremely rapidly, especially in the business world. The pressure on companies to carry out their business practices in ethical manners, which promote the wellbeing of the environment and society, is coming from all directions and all stakeholders. Alstom, a French multinational conglomerate operating in the rail transport and energy industry, is no exception to this norm. This company, which will be used as the case example in this thesis, is being brought to bay in terms of engaging in CSR practices and practicing business with high ethics. It is surely not a negatively conceived phenomenon that CSR is being put on a pedestal – quite the opposite. Instead of corporations practicing CSR only to meet their stakeholder requirements through practicing window dressing, many corporations actually strive to benefit from the practice of corporate social business. In addition to bringing benefit to externals a corporation such as Alstom itself can benefit from being involved in CSR. The purpose of this thesis is to evaluate the current strategic values and the future perspectives of CSR at Alstom and moreover the added value which the practice of CSR could bring Alstom as a business. A set of perspectives from a futures studies viewpoint is looked at, with critical examination of the company’s current corporate practices as well as the CSR related studies and theories written for corporations. Through this, some solutions and practices will be suggested to Alstom in order for it to fully utilize the potential of corporate social business and the value it can bring in the most probable futures that the company is expected to face. By utilizing the Soft Systems Methodology (SSM), a method mainly used in organizations to solve problematic issues in management and policy contexts, a process is developed to see what improvements could be of help in improving Alstom and its way towards involving CSR in its business practices even more than it currently does. Alstom is already deeply involved in the practicing of CSR and its vision has a strong emphasis on this popular concept of today. In order to stay in the game and to use CSR as a competitive advantage to the company, Alstom ought to embed corporate social practices even deeper in its organizational culture by using them as a tool to reduce risk and costs, increasing employee commitment and customer loyalty and to attract socially responsible investors, just to name a few. CSR as a concept is seen to have great potential in the future, an opportunity Alstom will not miss.

Threat modeling a factory environment using Microsoft Security Development Lifecycle methodology

The number of security violations is increasing and a security breach could have irreversible impacts to business. There are several ways to improve organization security, but some of them may be difficult to comprehend. This thesis demystifies threat modeling as part of secure system development. Threat modeling enables developers to reveal previously undetected security issues from computer systems. It offers a structured approach for organizations to find and address threats against vulnerabilities. When implemented correctly threat modeling will reduce the amount of defects and malicious attempts against the target environment. In this thesis Microsoft Security Development Lifecycle (SDL) is introduced as an effective methodology for reducing defects in the target system. SDL is traditionally meant to be used in software development, principles can be however partially adapted to IT-infrastructure development. Microsoft threat modeling methodology is an important part of SDL and it is utilized in this thesis to find threats from the Acme Corporation’s factory environment. Acme Corporation is used as a pseudonym for a company providing high-technology consumer electronics. Target for threat modeling is the IT-infrastructure of factory’s manufacturing execution system. Microsoft threat modeling methodology utilizes STRIDE –mnemonic and data flow diagrams to find threats. Threat modeling in this thesis returned results that were important for the organization. Acme Corporation now has more comprehensive understanding concerning IT-infrastructure of the manufacturing execution system. On top of vulnerability related results threat modeling provided coherent views of the target system. Subject matter experts from different areas can now agree upon functions and dependencies of the target system. Threat modeling was recognized as a useful activity for improving security.

Dependency of military capabilities on technological development

Our goal is to get better understanding of different kind of dependencies behind the high-level capability areas. The models are suitable for investigating present state capabilities or future developments of capabilities in the context of technology forecasting. Three levels are necessary for a model describing effects of technologies on military capabilities. These levels are capability areas, systems and technologies. The contribution of this paper is to present one possible model for interdependencies between technologies. Modelling interdependencies between technologies is the last building block in constructing a quantitative model for technological forecasting including necessary levels of abstraction. This study supplements our previous research and as a result we present a model for the whole process of capability modelling. As in our earlier studies, capability is defined as the probability of a successful task or operation or proper functioning of a system. In order to obtain numerical data to demonstrate our model, we conducted a questionnaire to a group of defence technology researchers where interdependencies between seven representative technologies were inquired. Because of a small number of participants in questionnaires and general uncertainties concerning subjective evaluations, only rough conclusions can be made from the numerical results

A software engineering approach to distributed systems for composite modeling

The goal of this thesis is to define and validate a software engineering approach for the development of a distributed system for the modeling of composite materials, based on the analysis of various existing software development methods. We reviewed the main features of: (1) software engineering methodologies; (2) distributed system characteristics and their effect on software development; (3) composite materials modeling activities and the requirements for the software development. Using the design science as a research methodology, the distributed system for creating models of composite materials is created and evaluated. Empirical experiments which we conducted showed good convergence of modeled and real processes. During the study, we paid attention to the matter of complexity and importance of distributed system and a deep understanding of modern software engineering methods and tools.