Probiotic interventions in infancy: Benefit and Safety Assessment of Extended Applications

Immaturity of the gut barrier system in the newborn has been seen to underlie a number of chronic diseases originating in infancy and manifesting later in life. The gut microbiota and breast milk provide the most important maturing signals for the gut-related immune system and reinforcement of the gut mucosal barrier function. Recently, the composition of the gut microbiota has been proposed to be instrumental in control of host body weight and metabolism as well as the inflammatory state characterizing overweight and obesity. On this basis, inflammatory Western lifestyle diseases, including overweight development, may represent a potential target for probiotic interventions beyond the well documented clinical applications. The purpose of the present undertaking was to study the efficacy and safety of perinatal probiotic intervention. The material comprised two ongoing, prospective, double-blind NAMI (Nutrition, Allergy, Mucosal immunology and Intestinal microbiota) probiotic interventions. In the mother-infant nutrition and probiotic study altogether 256 women were randomized at their first trimester of pregnancy into a dietary intervention and a control group. The intervention group received intensive dietary counselling provided by a nutritionist, and were further randomized at baseline, double-blind, to receive probiotics (Lactobacillus rhamnosus GG and Bifidobacterium lactis) or placebo. The intervention period extended from the first trimester of pregnancy to the end of exclusive breastfeeding. In the allergy prevention study altogether 159 women were randomized, double-blind, to receive probiotics (Lactobacillus rhamnosus GG) or placebo 4 weeks before expected delivery, the intervention extending for 6 months postnatally. Additionally, patient data on all premature infants with very low birth weight (VLBW) treated in the Department of Paediatrics, Turku University Hospital, during the years 1997 - 2008 were utilized. The perinatal probiotic intervention reduced the risk of gestational diabetes mellitus (GDM) in the mothers and perinatal dietary counselling reduced that of fetal overgrowth in GDM-affected pregnancies. Early gut microbiota modulation with probiotics modified the growth pattern of the child by restraining excessive weight gain during the first years of life. The colostrum adiponectin concentration was demonstrated to be dependent on maternal diet and nutritional status during pregnancy. It was also higher in the colostrum received by normal-weight compared to overweight children at the age of 10 years. The early perinatal probiotic intervention and the postnatal probiotic intervention in VLBW infants were shown to be safe. To conclude, the findings in this study provided clinical evidence supporting the involvement of the initial microbial and nutritional environment in metabolic programming of the child. The manipulation of early gut microbial communities with probiotics might offer an applicable strategy to impact individual energy homeostasis and thus to prevent excessive body-weight gain. The results add weight to the hypothesis that interventions aiming to prevent obesity and its metabolic consequences later in life should be initiated as early as during the perinatal period.

Centralized Motion Control of a Linear Tooth Belt Drive: Analysis of the Performance and Limitations

A centralized robust position control for an electrical driven tooth belt drive is designed in this doctoral thesis. Both a cascaded control structure and a PID based position controller are discussed. The performance and the limitations of the system are analyzed and design principles for the mechanical structure and the control design are given. These design principles are also suitable for most of the motion control applications, where mechanical resonance frequencies and control loop delays are present. One of the major challenges in the design of a controller for machinery applications is that the values of the parameters in the system model (parameter uncertainty) or the system model it self (non-parametric uncertainty) are seldom known accurately in advance. In this thesis a systematic analysis of the parameter uncertainty of the linear tooth beltdrive model is presented and the effect of the variation of a single parameter on the performance of the total system is shown. The total variation of the model parameters is taken into account in the control design phase using a Quantitative Feedback Theory (QFT). The thesis also introduces a new method to analyze reference feedforward controllers applying the QFT. The performance of the designed controllers is verified by experimentalmeasurements. The measurements confirm the control design principles that are given in this thesis.

Design and analysis of a transversal-flux switched-reluctance-linear-machine pole-pair

The Switched Reluctance technology is probably best suited for industrial low-speed or zerospeed applications where the power can be small but the torque or the force in linear movement cases might be relatively high. Because of its simple structure the SR-motor is an interesting alternative for low power applications where pneumatic or hydraulic linear drives are to be avoided. This study analyses the basic parts of an LSR-motor which are the two mover poles and one stator pole and which form the “basic pole pair” in linear-movement transversal-flux switchedreluctance motors. The static properties of the basic pole pair are modelled and the basic design rules are derived. The models developed are validated with experiments. A one-sided one-polepair transversal-flux switched-reluctance-linear-motor prototype is demonstrated and its static properties are measured. The modelling of the static properties is performed with FEM-calculations. Two-dimensional models are accurate enough to model the static key features for the basic dimensioning of LSRmotors. Three-dimensional models must be used in order to get the most accurate calculation results of the static traction force production. The developed dimensioning and modelling methods, which could be systematically validated by laboratory measurements, are the most significant contributions of this thesis.

Teaching mathematics and programming : new approaches with empirical evaluation

Programming and mathematics are core areas of computer science (CS) and consequently also important parts of CS education. Introductory instruction in these two topics is, however, not without problems. Studies show that CS students find programming difficult to learn and that teaching mathematical topics to CS novices is challenging. One reason for the latter is the disconnection between mathematics and programming found in many CS curricula, which results in students not seeing the relevance of the subject for their studies. In addition, reports indicate that students' mathematical capability and maturity levels are dropping. The challenges faced when teaching mathematics and programming at CS departments can also be traced back to gaps in students' prior education. In Finland the high school curriculum does not include CS as a subject; instead, focus is on learning to use the computer and its applications as tools. Similarly, many of the mathematics courses emphasize application of formulas, while logic, formalisms and proofs, which are important in CS, are avoided. Consequently, high school graduates are not well prepared for studies in CS. Motivated by these challenges, the goal of the present work is to describe new approaches to teaching mathematics and programming aimed at addressing these issues: Structured derivations is a logic-based approach to teaching mathematics, where formalisms and justifications are made explicit. The aim is to help students become better at communicating their reasoning using mathematical language and logical notation at the same time as they become more confident with formalisms. The Python programming language was originally designed with education in mind, and has a simple syntax compared to many other popular languages. The aim of using it in instruction is to address algorithms and their implementation in a way that allows focus to be put on learning algorithmic thinking and programming instead of on learning a complex syntax. Invariant based programming is a diagrammatic approach to developing programs that are correct by construction. The approach is based on elementary propositional and predicate logic, and makes explicit the underlying mathematical foundations of programming. The aim is also to show how mathematics in general, and logic in particular, can be used to create better programs.

Applications of graph transformation in tools for domain-specific modeling languages

The use of domain-specific languages (DSLs) has been proposed as an approach to cost-e ectively develop families of software systems in a restricted application domain. Domain-specific languages in combination with the accumulated knowledge and experience of previous implementations, can in turn be used to generate new applications with unique sets of requirements. For this reason, DSLs are considered to be an important approach for software reuse. However, the toolset supporting a particular domain-specific language is also domain-specific and is per definition not reusable. Therefore, creating and maintaining a DSL requires additional resources that could be even larger than the savings associated with using them. As a solution, di erent tool frameworks have been proposed to simplify and reduce the cost of developments of DSLs. Developers of tool support for DSLs need to instantiate, customize or configure the framework for a particular DSL. There are di erent approaches for this. An approach is to use an application programming interface (API) and to extend the basic framework using an imperative programming language. An example of a tools which is based on this approach is Eclipse GEF. Another approach is to configure the framework using declarative languages that are independent of the underlying framework implementation. We believe this second approach can bring important benefits as this brings focus to specifying what should the tool be like instead of writing a program specifying how the tool achieves this functionality. In this thesis we explore this second approach. We use graph transformation as the basic approach to customize a domain-specific modeling (DSM) tool framework. The contributions of this thesis includes a comparison of di erent approaches for defining, representing and interchanging software modeling languages and models and a tool architecture for an open domain-specific modeling framework that e ciently integrates several model transformation components and visual editors. We also present several specific algorithms and tool components for DSM framework. These include an approach for graph query based on region operators and the star operator and an approach for reconciling models and diagrams after executing model transformation programs. We exemplify our approach with two case studies MICAS and EFCO. In these studies we show how our experimental modeling tool framework has been used to define tool environments for domain-specific languages.

Software for design of experiments and response modelling of cake ltration applications

Filtration is a widely used unit operation in chemical engineering. The huge variation in the properties of materials to be ltered makes the study of ltration a challenging task. One of the objectives of this thesis was to show that conventional ltration theories are di cult to use when the system to be modelled contains all of the stages and features that are present in a complete solid/liquid separation process. Furthermore, most of the ltration theories require experimental work to be performed in order to obtain critical parameters required by the theoretical models. Creating a good overall understanding of how the variables a ect the nal product in ltration is somewhat impossible on a purely theoretical basis. The complexity of solid/liquid separation processes require experimental work and when tests are needed, it is advisable to use experimental design techniques so that the goals can be achieved. The statistical design of experiments provides the necessary tools for recognising the e ects of variables. It also helps to perform experimental work more economically. Design of experiments is a prerequisite for creating empirical models that can describe how the measured response is related to the changes in the values of the variable. A software package was developed that provides a ltration practitioner with experimental designs and calculates the parameters for linear regression models, along with the graphical representation of the responses. The developed software consists of two software modules. These modules are LTDoE and LTRead. The LTDoE module is used to create experimental designs for di erent lter types. The lter types considered in the software are automatic vertical pressure lter, double-sided vertical pressure lter, horizontal membrane lter press, vacuum belt lter and ceramic capillary action disc lter. It is also possible to create experimental designs for those cases where the variables are totally user de ned, say for a customized ltration cycle or di erent piece of equipment. The LTRead-module is used to read the experimental data gathered from the experiments, to analyse the data and to create models for each of the measured responses. Introducing the structure of the software more in detail and showing some of the practical applications is the main part of this thesis. This approach to the study of cake ltration processes, as presented in this thesis, has been shown to have good practical value when making ltration tests.

Software for design of experiments and response modelling of cake filtration applications

Filtration is a widely used unit operation in chemical engineering. The huge variation in the properties of materials to be ltered makes the study of ltration a challenging task. One of the objectives of this thesis was to show that conventional ltration theories are di cult to use when the system to be modelled contains all of the stages and features that are present in a complete solid/liquid separation process. Furthermore, most of the ltration theories require experimental work to be performed in order to obtain critical parameters required by the theoretical models. Creating a good overall understanding of how the variables a ect the nal product in ltration is somewhat impossible on a purely theoretical basis. The complexity of solid/liquid separation processes require experimental work and when tests are needed, it is advisable to use experimental design techniques so that the goals can be achieved. The statistical design of experiments provides the necessary tools for recognising the e ects of variables. It also helps to perform experimental work more economically. Design of experiments is a prerequisite for creating empirical models that can describe how the measured response is related to the changes in the values of the variable. A software package was developed that provides a ltration practitioner with experimental designs and calculates the parameters for linear regression models, along with the graphical representation of the responses. The developed software consists of two software modules. These modules are LTDoE and LTRead. The LTDoE module is used to create experimental designs for di erent lter types. The lter types considered in the software are automatic vertical pressure lter, double-sided vertical pressure lter, horizontal membrane lter press, vacuum belt lter and ceramic capillary action disc lter. It is also possible to create experimental designs for those cases where the variables are totally user de ned, say for a customized ltration cycle or di erent piece of equipment. The LTRead-module is used to read the experimental data gathered from the experiments, to analyse the data and to create models for each of the measured responses. Introducing the structure of the software more in detail and showing some of the practical applications is the main part of this thesis. This approach to the study of cake ltration processes, as presented in this thesis, has been shown to have good practical value when making ltration tests.

Linear-quadratic optimal control of descriptor systems

In recent years the analysis and synthesis of (mechanical) control systems in descriptor form has been established. This general description of dynamical systems is important for many applications in mechanics and mechatronics, in electrical and electronic engineering, and in chemical engineering as well. This contribution deals with linear mechanical descriptor systems and its control design with respect to a quadratic performance criterion. Here, the notion of properness plays an important role whether the standard Riccati approach can be applied as usual or not. Properness and non-properness distinguish between the cases if the descriptor system is exclusively governed by the control input or by its higher-order time-derivatives additionally. In the unusual case of non-proper systems a quite different problem of optimal control design has to be considered. Both cases will be solved completely.

Object-oriented Programming Applied to the Development of Structural Analysis and Optimization Software

This paper presents the development of a two-dimensional interactive software environment for structural analysis and optimization based on object-oriented programming using the C++ language. The main feature of the software is the effective integration of several computational tools into graphical user interfaces implemented in the Windows-98 and Windows-NT operating systems. The interfaces simplify data specification in the simulation and optimization of two-dimensional linear elastic problems. NURBS have been used in the software modules to represent geometric and graphical data. Extensions to the analysis of three-dimensional problems have been implemented and are also discussed in this paper.

Heat Source Estimation with the Conjugate Gradient Method in Inverse Linear Diffusive Problems

In this work, we present the solution of a class of linear inverse heat conduction problems for the estimation of unknown heat source terms, with no prior information of the functional forms of timewise and spatial dependence of the source strength, using the conjugate gradient method with an adjoint problem. After describing the mathematical formulation of a general direct problem and the procedure for the solution of the inverse problem, we show applications to three transient heat transfer problems: a one-dimensional cylindrical problem; a two-dimensional cylindrical problem; and a one-dimensional problem with two plates.

Roll-to-roll atomic layer deposition process for flexible electronics applications

Atomic Layer Deposition (ALD) is the technology of choice where very thin and highquality films are required. Its advantage is its ability to deposit dense and pinhole-free coatings in a controllable manner. It has already shown promising results in a range of applications, e.g. diffusion barrier coatings for OLED displays, surface passivation layers for solar panels. Spatial Atomic Layer Deposition (SALD) is a concept that allows a dramatic increase in ALD throughput. During the SALD process, the substrate moves between spatially separated zones filled with the respective precursor gases and reagents in such a manner that the exposure sequence replicates the conventional ALD cycle. The present work describes the development of a high-throughput ALD process. Preliminary process studies were made using an SALD reactor designed especially for this purpose. The basic properties of the ALD process were demonstrated using the wellstudied Al2O3 trimethyl aluminium (TMA)+H2O process. It was shown that the SALD reactor is able to deposit uniform films in true ALD mode. The ALD nature of the process was proven by demonstrating self-limiting behaviour and linear film growth. The process behaviour and properties of synthesized films were in good agreement with previous ALD studies. Issues related to anomalous deposition at low temperatures were addressed as well. The quality of the coatings was demonstrated by applying 20 nm of the Al2O3 on to polymer substrate and measuring its moisture barrier properties. The results of tests confirmed the superior properties of the coatings and their suitability for flexible electronics encapsulation. Successful results led to the development of a pilot scale roll-to-roll coating system. It was demonstrated that the system is able to deposit superior quality films with a water transmission rate of 5x10-6 g/m2day at a web speed of 0.25 m/min. That is equivalent to a production rate of 180 m2/day and can be potentially increased by using wider webs. State-of-art film quality, high production rates and repeatable results make SALD the technology of choice for manufacturing ultra-high barrier coatings for flexible electronics.

Modification of commercial poly-lactide for extrusion coated food packaging applications

Poly-L-lactide (PLLA) is a widely used sustainable and biodegradable alternative to replace synthetic non-degradable plastic materials in the packaging industry. Conversely, its processing properties are not always optimal, e.g. insufficient melt strength at higher temperatures (necessary in extrusion coating processes). This thesis reports on research to improve properties of commercial PLLA grade (3051D from NatureWorks), to satisfy and extend end-use applications, such as food packaging by blending with modified PLLA. Adjustment of the processability by chain branching of commercial poly-L-lactide initiated by peroxide was evaluated. Several well-defined branched structures with four arms (sPLLA) were synthesized using pentaerythritol as a tetra-functional initiator. Finally, several block copolymers consisting of polyethylene glycol and PLLA (i.e. PEGLA) were produced to obtain a well extruded material with improved heat sealing properties. Reactive extrusion of poly-L-lactide was carried out in the presence of 0.1, 0.3 and 0.5 wt% of various peroxides [tert-butyl-peroxybenzoate (TBPB), 2,5-dimethyl-2,5-(tert-butylperoxy)-hexane (Lupersol 101; LOL1) and benzoyl peroxide (BPO)] at 190C. The peroxide-treated PLLAs showed increased complex viscosity and storage modulus at lower frequencies, indicating the formation of branched/cross linked architectures. The material property changes were dependent on the peroxide, and the used peroxide concentration. Gel fraction analysis showed that the peroxides, afforded different gel contents, and especially 0.5 wt% peroxide, produced both an extremely high molar mass, and a cross linked structure, not perhaps well suited for e.g. further use in a blending step. The thermal behavior was somewhat unexpected as the materials prepared with 0.5 wt% peroxide showed the highest ability for crystallization and cold crystallization, despite substantial cross linking. The peroxide-modified PLLA, i.e. PLLA melt extruded with 0.3 wt% of TBPB and LOL1 and 0.5 wt% BPO was added to linear PLLA in ratios of 5, 15 and 30 wt%. All blends showed increased zero shear viscosity, elastic nature (storage modulus) and shear sensitivity. All blends remained amorphous, though the ability of annealing was improved slightly. Extrusion coating on paperboard was conducted with PLLA, and peroxide-modified PLLA blends (90:10). All blends were processable, but only PLLA with 0.3 wt% of LOL1 afforded a smooth high quality surface with improved line speed. Adhesion levels between fiber and plastic, as well as heat seal performance were marginally reduced compared with pure 3051D. The water vapor transmission measurements (WVTR) of the blends containing LOL1 showed acceptable levels, only slightly lower than for comparable PLLA 3051D. A series of four-arm star-shaped poly-L-lactide (sPLLA) with different branch length was synthesized by ring opening polymerization (ROP) of L-lactide using pentaerythritol as initiator and stannous octoate as catalyst. The star-shaped polymers were further blended with its linear resin and studied for their melt flow and thermal properties. Blends containing 30 wt% of sPLLA with low molecular weight (30 wt%; Mwtotal: 2500 g mol-1 and 15000 g mol-1) showed lower zero shear viscosity and significantly increased shear thinning, while at the same time slightly increased crystallization of the blend. However, the amount of crystallization increased significantly with the higher molecular weight sPLLA, therefore the star-shaped structure may play a role as nucleating agent. PLLA-polyethylene glycol–PLLA triblock copolymers (PEGLA) with different PLLA block length were synthesized and their applicability as blends with linear PLLA (3051D NatureWorks) was investigated with the intention of improving heat-seal and adhesion properties of extrusion-coated paperboard. PLLA-PEG-PLLA was obtained by ring opening polymerization (ROP) of L-lactide using PEG (molecular weight 6000 g mol-1) as an initiator, and stannous octoate as catalyst. The structures of the PEGLAs were characterized by proton nuclear magnetic resonance spectroscopy (1H-NMR). The melt flow and thermal properties of all PEGLAs and their blends were evaluated using dynamic rheology, and differential scanning calorimeter (DSC). All blends containing 30 wt% of PEGLAs showed slightly higher zero shear viscosity, higher shear thinning and increased melt elasticity (based on tan delta). Nevertheless, no significant changes in thermal properties were distinguished. High molecular weight PEGLAs were used in extrusion coating line with 3051D without problems.

Adopting the Vaadin Java framework to rebuild VTT’s Web Interfaces and Database Applications

With the growth in new technologies, using online tools have become an everyday lifestyle. It has a greater impact on researchers as the data obtained from various experiments needs to be analyzed and knowledge of programming has become mandatory even for pure biologists. Hence, VTT came up with a new tool, R Executables (REX) which is a web application designed to provide a graphical interface for biological data functions like Image analysis, Gene expression data analysis, plotting, disease and control studies etc., which employs R functions to provide results. REX provides a user interactive application for the biologists to directly enter the values and run the required analysis with a single click. The program processes the given data in the background and prints results rapidly. Due to growth of data and load on server, the interface has gained problems concerning time consumption, poor GUI, data storage issues, security, minimal user interactive experience and crashes with large amount of data. This thesis handles the methods by which these problems were resolved and made REX a better application for the future. The old REX was developed using Python Django and now, a new programming language, Vaadin has been implemented. Vaadin is a Java framework for developing web applications and the programming language is extremely similar to Java with new rich components. Vaadin provides better security, better speed, good and interactive interface. In this thesis, subset functionalities of REX was selected which includes IST bulk plotting and image segmentation and implemented those using Vaadin. A code of 662 lines was programmed by me which included Vaadin as the front-end handler while R language was used for back-end data retrieval, computing and plotting. The application is optimized to allow further functionalities to be migrated with ease from old REX. Future development is focused on including Hight throughput screening functions along with gene expression database handling

Automatic Structure Generation using Genetic Programming and Fractal Geometry

Three dimensional model design is a well-known and studied field, with numerous real-world applications. However, the manual construction of these models can often be time-consuming to the average user, despite the advantages o ffered through computational advances. This thesis presents an approach to the design of 3D structures using evolutionary computation and L-systems, which involves the automated production of such designs using a strict set of fitness functions. These functions focus on the geometric properties of the models produced, as well as their quantifiable aesthetic value - a topic which has not been widely investigated with respect to 3D models. New extensions to existing aesthetic measures are discussed and implemented in the presented system in order to produce designs which are visually pleasing. The system itself facilitates the construction of models requiring minimal user initialization and no user-based feedback throughout the evolutionary cycle. The genetic programming evolved models are shown to satisfy multiple criteria, conveying a relationship between their assigned aesthetic value and their perceived aesthetic value. Exploration into the applicability and e ffectiveness of a multi-objective approach to the problem is also presented, with a focus on both performance and visual results. Although subjective, these results o er insight into future applications and study in the fi eld of computational aesthetics and automated structure design.

Computation and Analysis of Multiple Structural-Change Models

In a recent paper, Bai and Perron (1998) considered theoretical issues related to the limiting distribution of estimators and test statistics in the linear model with multiple structural changes. In this companion paper, we consider practical issues for the empirical applications of the procedures. We first address the problem of estimation of the break dates and present an efficient algorithm to obtain global minimizers of the sum of squared residuals. This algorithm is based on the principle of dynamic programming and requires at most least-squares operations of order O(T 2) for any number of breaks. Our method can be applied to both pure and partial structural-change models. Secondly, we consider the problem of forming confidence intervals for the break dates under various hypotheses about the structure of the data and the errors across segments. Third, we address the issue of testing for structural changes under very general conditions on the data and the errors. Fourth, we address the issue of estimating the number of breaks. We present simulation results pertaining to the behavior of the estimators and tests in finite samples. Finally, a few empirical applications are presented to illustrate the usefulness of the procedures. All methods discussed are implemented in a GAUSS program available upon request for non-profit academic use.