Towards targeting of adaptive immune responses in rheumatoid arthritis

The therapeutic options for rheumatoid arthritis (RA) have increased immensely in the past two decades and resulted in improvements in outcome and quality of life. Especially, the arrival of biological and targeted synthetic disease-modifying anti-rheumatic drugs, with therapeutic targets ranging from cytokines (e.g. tumor necrosis factor to CD20 on B-cells, has dramatically improved the life of patients as exemplified by improved disease signs and symptoms together with less structural damage. However, these therapies have been proven not to be curative. Therefore, there is a clear need for a better understanding of the under- lying pathophysiology, including the contribution of the adaptive immune system and its window of opportunity for treatment in RA patients and individuals at risk of developing RA. Thus, the overarching aim of this thesis was to gain more knowledge on the adaptive immune response in different phases of RA and in various locations; ranging from the early at-risk phase to clinically apparent RA, from studies in blood-only to other bodily compartments, and from T-cells to B-cells

Qualitative modeling in computational systems biology

The human body is composed of a large collection of cells,\the building blocks of life". In each cell, complex networks of biochemical processes contribute in maintaining a healthy organism. Alterations in these biochemical processes can result in diseases. It is therefore of vital importance to know how these biochemical networks function. Simple reasoning is not su±cient to comprehend life's complexity. Mathematical models have to be used to integrate information from various sources for solving numerous biomedical research questions, the so-called systems biology approach, in which quantitative data are scarce and qualitative information is abundant. Traditional mathematical models require quantitative information. The lack in ac- curate and su±cient quantitative data has driven systems biologists towards alternative ways to describe and analyze biochemical networks. Their focus is primarily on the anal- ysis of a few very speci¯c biochemical networks for which accurate experimental data are available. However, quantitative information is not a strict requirement. The mutual interaction and relative contribution of the components determine the global system dy- namics; qualitative information is su±cient to analyze and predict the potential system behavior. In addition, mathematical models of biochemical networks contain nonlinear functions that describe the various physiological processes. System analysis and parame- ter estimation of nonlinear models is di±cult in practice, especially if little quantitative information is available. The main contribution of this thesis is to apply qualitative information to model and analyze nonlinear biochemical networks. Nonlinear functions are approximated with two or three linear functions, i.e., piecewise-a±ne (PWA) functions, which enables qualitative analysis of the system. This work shows that qualitative information is su±cient for the analysis of complex nonlinear biochemical networks. Moreover, this extra information can be used to put relative bounds on the parameter values which signi¯cantly improves the parameter estimation compared to standard nonlinear estimation algorithms. Also a PWA parameter estimation procedure is presented, which results in more accurate parameter estimates than conventional parameter estimation procedures. Besides qualitative analysis with PWA functions, graphical analysis of a speci¯c class of systems is improved for a certain less general class of systems to yield constraints on the parameters. As the applicability of graphical analysis is limited to a small class of systems, graphical analysis is less suitable for general use, as opposed to the qualitative analysis of PWA systems. The technological contribution of this thesis is tested on several biochemical networks that are involved in vascular aging. Vascular aging is the accumulation of changes respon- sible for the sequential alterations that accompany advancing age of the vascular system and the associated increase in the chance of vascular diseases. Three biochemical networks are selected from experimental data, i.e., remodeling of the extracellular matrix (ECM), the signal transduction pathway of Transforming Growth Factor-¯1 (TGF-¯1) and the unfolded protein response (UPR). The TGF-¯1 model is constructed by means of an extensive literature search and con- sists of many state equations. Model reduction (the quasi-steady-state approximation) reduces the model to a version with only two states, such that the procedure can be visual- ized. The nonlinearities in this reduced model are approximated with PWA functions and subsequently analyzed. Typical results show that oscillatory behavior can occur in the TGF-¯1 model for speci¯c sets of parameter values. These results meet the expectations of preliminary experimental results. Finally, a model of the UPR has been formulated and analyzed similarly. The qualitative analysis yields constraints on the parameter values. Model simulations with these parameter constraints agree with experimental results

Vegetation development in sown field margins and on adjacent ditch banks

The creation of temporal and newly sown field margins for 6 years is a common agri-environment scheme (AES) in the Netherlands. Conservation profits resulting from AES vary over different areas and need further studying. We examined plant species richness in such field margins and adjacent ditch banks in the province of Zeeland, where these linear elements do not experience plant biomass removal after mowing as management strategy. First, during 2 years, we inventoried field margins sown with a wildflower mixture and related the species composition and richness to the age of the margins. In a second assessment, we studied plant species richness on ditch banks protected from arable fields by these margins. Major clusters in a principal component analysis (PCA) on species composition in the field margins showed a succession from sown and ruderal annual species (year 1), to sown perennial species (year 2) and ending with a dominance by tussock forming grass species and Urtica dioica (year 5–6). Total plant species richness decreased with increasing age of the margins, and this was caused by the combination of a decline in sown species and a stable number of not-sown species. The presence of field margins during several years did not result in an increase in plant species richness on adjacent ditch banks. In both the field margins and on the ditch banks, mowing management is not followed by the removal of the cuttings. For plant conservation, the results of these field margins are disappointing, probably due to the lack of a proper management. Therefore, we recommend implementing a hay-making and opening management, to increase plant richness and to reduce noxious weeds in the margins and on the ditch bank

Using eggshell membranes as a DNA source for population genetic research

In the context of population genetic research, a faster and less invasive method of DNA sampling would allow large-scale assessments of genetic diversity and genetic differentiation with the help of volunteer observers. The aim of this study was to investigate the usefulness of eggshell membranes as a DNA source for population genetic research, by addressing eggshell membrane DNA quality, degeneration and cross-contamination. To this end, a comparison was made with blood-derived DNA samples. We have demonstrated 100% successful DNA extraction from post-hatched Black-tailed Godwit (Limosa limosa) eggshell membranes as well as from blood samples. Using 11 microsatellite loci, DNA amplification success was 99.1% for eggshell membranes and 97.7% for blood samples. Genetic information within eggshell membrane DNA in comparison to blood DNA was not affected (F-ST = -0.01735, P = 0.999) by degeneration or possible cross-contamination. Furthermore, neither degeneration nor cross-contamination was apparent in total genotypic comparison of eggshell membrane DNA and blood sample DNA. Our research clearly illustrates that eggshell membranes can be used for population genetic research

On the Races of Patagonia.

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Robotic bird

A robotic bird, comprising - a body, extending along a longitudinal axis between a head and a tail, - two fixed wings, connected to the body on opposite sides of the body, wherein each wing has a vertical cross-sectional shape along the longitudinal axis of the body, which gradually transforms in a direction away from the body, from a first shape which is convex at an upper side and concave at a lower side to a second shape which is convex at an upper side and convex at a lower side