The plant kingdom has evolved an enormous number of chemically diverse metabolites that protect plants from biotic and abiotic stresses. The large number of metabolites in a given plant indicates... Show moreThe plant kingdom has evolved an enormous number of chemically diverse metabolites that protect plants from biotic and abiotic stresses. The large number of metabolites in a given plant indicates interactions between metabolites are very likely. The co-occurrence of plant metabolites comprise a natural background where these metabolites have to function and this is often overlooked or ignored in ecological studies. The main goal of this thesis is to understand the importance of metabolite interactions I used assays with a generalist herbivore to study the interactions between chlorogenic acid (CGA), pyrrolizidine alkaloids (PAs) and fractions from Jacobaea plants. I found that PA free bases, PA N-oxides (the oxidized form of free base) and CGA decreased thrips survival. Although PA free bases and CGA decreased thrips survival, the combination of the two toxins was less toxic than the single toxins. In contrast, the combination of PA N-oxides with CGA enhanced the toxicity against thrips in a synergistic way. Adding PAs to different plant fractions showed that metabolite interactions on thrips survival are common as in all tested combinations we found antagonistic and synergistic effects. Clearly, bioactivity of a metabolite is strongly dependent upon the co-occurrence of metabolites in the plant cell. Show less
With the ever-growing amount of image data on the web, much attention has been devoted to large scale image search. It is one of the most challenging problems in computer vision for several... Show moreWith the ever-growing amount of image data on the web, much attention has been devoted to large scale image search. It is one of the most challenging problems in computer vision for several reasons. First, it must address various appearance transformations such as changes in perspective, rotation and scale existing in the huge amount of image data. Second, it needs to minimize memory requirements and computational cost when generating image representations. Finally, it needs to construct an efficient index space and a suitable similarity measure to reduce the response time to the users. This thesis aims to provide robust image representations that are less sensitive to above mentioned appearance transformations and are suitable for large scale image retrieval. Although this thesis makes a substantial number of contributions to large scale image retrieval, we also presented additional challenges and future research based on the contributions in this thesis. Show less
The presence of a small parameter can reduce the complexity of the stability analysis of pattern solutions. This reduction manifests itself through the complex-analytic Evans function, which... Show moreThe presence of a small parameter can reduce the complexity of the stability analysis of pattern solutions. This reduction manifests itself through the complex-analytic Evans function, which vanishes on the spectrum of the linearization about the pattern. For certain 'slowly linear' prototype models it has been shown, via geometric arguments, that the Evans function factorizes in accordance with the scale separation. This leads to asymptotic control over the spectrum through simpler, lower-dimensional eigenvalue problems. Recently, the geometric factorization procedure has been generalized to homoclinic pulse solutions in slowly nonlinear reaction-di ffusion systems. In this thesis we study periodic pulse solutions in the slowly nonlinear regime. This seems a straightforward extension. However, the geometric factorization method fails and due to translational invariance there is a curve of spectrum attached to the origin, whereas for homoclinic pulses there is only a simple eigenvalue residing at 0. We develop an alternative, analytic factorization method that works for periodic structures in the slowly nonlinear setting. We derive explicit formulas for the factors of the Evans function, which yields asymptotic spectral control. Moreover, we obtain a leading-order expression for the critical spectral curve attached to origin. Together these approximation results lead to explicit stability criteria. Show less
The theoretical description of fermionic system with strong interaction is a very challenging open problem in physics. The most notable (but far from the only) experimental realization of this... Show moreThe theoretical description of fermionic system with strong interaction is a very challenging open problem in physics. The most notable (but far from the only) experimental realization of this type of systems are the cuprate superconductors which have zero electric resistivity. Even if onehas a good microscopic model for the description of these materials it is very hard to translate it to macroscopic observables which in principle can be experimentally checked. The problem is that in case of a relevant interaction one can not Taylor expand in the coupling constant in the low-energy regime in which we are most interested. On the other hand, because of the fermion sign problem Monte Carlo numerical techniques (which are succesful with bosonic models) do not work for fermions at finite density. This thesis is devoted to the applications of several methods to the research area described above. The common theme of these techniques is that they are (partly) motivated from high-energy physics: the research area which deals with particle physics, string theory etc. Show less
Unambiguous sequence variant descriptions are important in reporting the outcome of clinical diagnostic DNA tests. The standard nomenclature of the Human Genome Variation Society (HGVS)... Show moreUnambiguous sequence variant descriptions are important in reporting the outcome of clinical diagnostic DNA tests. The standard nomenclature of the Human Genome Variation Society (HGVS) describes the observed variant sequence relative to a given reference sequence. We propose an efficient algorithm for the extraction of HGVS descriptions from two DNA sequences. Our algorithm is able to compute the HGVS~descriptions of complete chromosomes or other large DNA strings in a reasonable amount of computation time and its resulting descriptions are relatively small. Additional applications include updating of gene variant database contents and reference sequence liftovers. Next, we adapted our method for the extraction of descriptions for protein sequences in particular for describing frame shifted variants. We propose an addition to the HGVS nomenclature for accommodating the (complex) frame shifted variants that can be described with our method. Finally, we applied our method to generate descriptions for Short Tandem Repeats (STRs), a form of self-similarity. We propose an alternative repeat variant that can be added to the existing HGVS nomenclature. The final chapter takes an explorative approach to classification in large cohort studies. We provide a ``cross-sectional'' investigation on this data to see the relative power of the different groups. Show less
Proteins play a crucial role in life, taking part in all vital process in the body, and are therefore used as therapeutic agents in a diverse range of biomedical applications. When... Show more Proteins play a crucial role in life, taking part in all vital process in the body, and are therefore used as therapeutic agents in a diverse range of biomedical applications. When administrated into bodily fluids, most native proteins are prone to degradation or inactivation process. The challenges of protein delivery are overcoming poor stability, low permeability toward cell membrane. Among all existing materials for protein delivery, mesoporous silica nanoparticles (MSNs) are one of the most promising intracellular nanocarriers due to its key properties: biocompatible, straightforward synthesis, and surface modification. For various biomedical applications, monodisperse MSNs with a particle size in the 50-200 nm range,3 controllable surface chemistry,4 and a large pore size (> 5 nm) are desired. This thesis presents a new method to synthesize large disc-like pore (10 ± 1 nm) containing MSNs with an elongated cuboidal-like geometry (90 × 43 nm), which effectively encapsulate and release proteins. Show less
Collaborative innovation processes in unpredictable environments are a challenge for traditional management. But new demands in a global digital society push public and corporate leadership to... Show moreCollaborative innovation processes in unpredictable environments are a challenge for traditional management. But new demands in a global digital society push public and corporate leadership to collaborate ad hoc, without predictable goals and planned working rules. In this study, an actor-network approach (ANT) is combined with critical incident technique (CIT) to elaborate dynamic network principles for a new real-time foresight (RTF). Real-time foresight replaces traditional planning and strategic management in ad hoc multi-sector collaborations. Although ANT originates from science and technologies studies, it is here applied to a management problem due to ist ability to merge voluntaristic and evolutionary managerial components and micro- and macro perspectives. The investigation is placed in an exemplary management field of high dynamics: global disaster management. From process analysis and from comparison of three dynamic innovation networks that emerged around Indian coastal villages after Tsunami 2004, five dynamic network patterns are obtained which underly successful collaborative innovation processes. These dynamic structures build the agenda for a new real-time foresight, and for an instrument to evaluate in real-time the emergence of dynamic innovation networks (DINs). Show less
The aim of this thesis is to understand the epidemiology, treatment and outcomes of specialized burn care in The Netherlands. This thesis is mainly based on historical data of the burn... Show more The aim of this thesis is to understand the epidemiology, treatment and outcomes of specialized burn care in The Netherlands. This thesis is mainly based on historical data of the burn centre in Rotterdam from 1986, combined with historical data from the burn centres in Groningen and Beverwijk from 1995-2009 and the common Dutch Burns Registration (NBR) R3 from 2009. This dissertation consists of three parts: part 1: Epidemiology Part 2: Treatment part 3: Results Part 1 Epidemiology In two chapters trends in severe burns in the Netherlands and epidemiology of children admitted to the Dutch Burn Centres and changes in referral influence admittance rates in burn centres are described . Part 2 Treatment Chapter 4 describes the use of modern wound dressings (hydrofibres) where a reduction in the number of operations to be carried out was seen in comparison with the ointment treatment with silver sulfadiazine in second degree burns. Chapter 5 describes the results of bacteriological cultures at admission, which is used an extensive database from 1987. Part 3 Results In 3 chapters the predictive value of a scoring system and the mortality in burn centers in The Netherlands are described. Show less
In this thesis, metabolomics is used to study the role of the host-virus interaction on a metabolic level. A special emphasis is directed on the role of inflammation and oxidative stress on... Show more In this thesis, metabolomics is used to study the role of the host-virus interaction on a metabolic level. A special emphasis is directed on the role of inflammation and oxidative stress on the metabolic level, as part of the innate immune response against viral infection. We chose respiratory syncytial virus (RSV) and hepatitis B virus (HBV) as candidate viruses to metabolically study their role in acute respiratory infection and chronic hepatitis B infection. Secondly we also investigated infant metabolic and immunological consequences of in utero exposure to antiretroviral intervention and human immunodeficiency virus (HIV). Collectively, established targeted metabolomics approaches in conjunction with newly developed metabolomics methodologies and complemented with other “omics” techniques, were used to address pertinent questions related to host metabolic functioning and alterations during viral infection. In vitro RSV studies together with in vivo patient based studies relating to chronic HBV infection and in utero exposure too antiretroviral and HIV were used to address these questions. The work is divided into three research parts containing: i. the analytical methodology development work, ii. in vitro based metabolomics and iii. patient based metabolomics. Show less
In this thesis I studied the functions of the zebrafish orthologs of the human TLR5 and TLR2 genes that were shown to be responsible for recognition of bacterial flagellin and a broad spectrum... Show moreIn this thesis I studied the functions of the zebrafish orthologs of the human TLR5 and TLR2 genes that were shown to be responsible for recognition of bacterial flagellin and a broad spectrum of bacterial cell wall components, respectively. One of the focal points of this thesis is the difference at the transcriptomic level of the downstream pathway of the TLR5 and TLR2 receptors and the roles of TLR signaling in host innate immune responses to infection by Mycobacterium marinum, a close relative to Mycobacterium tuberculosis and a natural pathogen of zebrafish. The new possibilities for analysis of transcriptomes using RNA deep sequencing make it highly attractive to analyze the responses of an entire test animal model at the system biology level. Furthermore, we used genetic knockdown and knockout tools to further analyze the function of TLR5 and TLR2 and downstream signaling partners in innate immunity, infectious disease and insulin resistance. Show less
The nature of the Dark Matter is one of the biggest open questions in modern cosmology and particle physics. The work in this thesis concerns a search for the observational effects of one... Show moreThe nature of the Dark Matter is one of the biggest open questions in modern cosmology and particle physics. The work in this thesis concerns a search for the observational effects of one particular class of hypothetical Dark Matter particles, namely those that are allowed to decay. In decaying, X-ray photons are emitted and should be observable. One part of the thesis details the discovery of a potential Dark Matter decay signal in X-ray spectra of galaxies and galaxy clusters, and the subsequent efforts to identify its origin. To this end archival data and new observations are compared to the respective Dark Matter masses of the observed objects. Interpretations of the signal as an instrumental effect, or due to regular astrophysical processes are unsatisfactory. Although the Dark Matter interpretation remains plausible, definitive conclusions about the origin of the signal can not be drawn yet and will require measurements by next generation observatories. The last chapter of the thesis contains the proof-of-concept of a novel technique to search for such weak signals that combines increased statistical power with the ability to determine the physical origin of a signal, while avoiding some of the disadvantages of traditional methods. Show less
Many scientists are focussed on building models. We nearly process all information we perceive to a model. There are many techniques that enable computers to build models as well. The field... Show more Many scientists are focussed on building models. We nearly process all information we perceive to a model. There are many techniques that enable computers to build models as well. The field of research that develops such techniques is called Machine Learning. Many research is devoted to develop computer programs capable of building models (algorithms). Many of such algorithms exist, and these often consist of various options that subtly influence performance (parameters). Furthermore, there is mathematical proof that there exists no single algorithm that works well on every dataset. This complicates the task of selecting the right algorithm for a given task. The field of meta-learning aims to resolve these problems. The purpose is to determine what kind of algorithms work well on which datasets. In order to do so, we developed OpenML. This is an online database on which researches can share experimental results amongst each other, potentially scaling up the size of meta-learning studies. Having earlier experimental results freely accessible and reusable for others, it is no longer required to conduct time expensive experiments. Rather, researchers can answer such experimental questions by a simple database look-up. This thesis addresses how OpenML can be used to answer fundamental meta-learning questions. Show less
The work described in this thesis is mainly focusing on setting up and application of a quantitative activity‐based proteasome profiling method. Chapter 1 provides a general introduction on the... Show moreThe work described in this thesis is mainly focusing on setting up and application of a quantitative activity‐based proteasome profiling method. Chapter 1 provides a general introduction on the ubiquitin proteasome system (UPS) and activity‐based proteasome profiling. Chapter 2 is a literature review of some new achievements in the activity‐based protein profiling field in the recent years, focusing on application in biochemistry, molecular and cellular biology, medicinal chemistry, pathology, physiology and pharmacology research. Chapter 3 is a protocol for performing quantitative activity‐based proteasome profiling experiments. In the protocol, both high throughput fluorescent ABPP and biotinylated probe plus LC/MS approaches are described. Chapter 4 is a brief technical report about bioorthogonal chemistry in ABPP. The commonly used secondary azide group is compared with a primary azide group in proteasome ABPs performing Cu(I) catalyzed azide‐alkyne cycloaddition and Staudinger‐Bertozzi reaction under native/denatured protein conditions Chapter 5 is focusing on the application of quantitative activity‐based proteasome profiling in the prognosis of cancer therapeutics. A combination of ABPP and global proteomics is performed to elucidate the bortezomib sensitivity and resistance mechanisms in leukemia and solid tumor cells. Chapter 6 describes the characterization of the newly discovered proteasome subunit β5t by ABPP and LC/MS proteomics. The subunit is proven to be catalytically active. A hydrophilic Thr residue on the P2 position of the proteasome inhibitor improves the inhibitory efficiency of β5t, which indicates it might prefer to cleave hydrophilic peptides. Chapter 7 describes the identification of O‐GlcNAcylation modifications on the ubiquitin receptor protein hHR23B and characterization of how the sugar moiety influences the conformation and functions of the protein. Show less
Preferences have always been present in many tasks in our daily lives. Buying the right car, choosing a suitable house or even deciding on the food to eat, are trivial examples of decisions that... Show morePreferences have always been present in many tasks in our daily lives. Buying the right car, choosing a suitable house or even deciding on the food to eat, are trivial examples of decisions that reveal information, explicitly or implicitly, about our preferences. The recent trend of collecting increasing amounts of data is also true for preference data. Extracting and modeling preferences can provide us with invaluable information about the choices of groups or individuals. In areas like e-commerce, which typically deal with decisions from thousands of users, the acquisition of preferences can be a difficult task. For these reasons, artificial intelligence (in particular, machine learning) methods have been increasingly important to the discovery and automatic learning of models about preferences. In this Ph.D. project, several approaches were analyzed and proposed to deal with the LR problem. Most of which has focused on pattern mining methods. Show less
Kinases play a role in many diseases including cancer, diabetes and infection diseases. Therefore, kinases are interesting drug targets. Inhibitors for some kinases are already in use as... Show moreKinases play a role in many diseases including cancer, diabetes and infection diseases. Therefore, kinases are interesting drug targets. Inhibitors for some kinases are already in use as clinical drugs, however due to resistance and side effects, but also to target kinases related to diseases for which there is currently no treatment, research on the discovery of new classes of kinase inhibitors is imperative. To achieve this, not only new inhibitor classes need to be designed and synthesized, but also tools to profile kinases in physiological context and to determine the selectivity of inhibitors are required. The research in this thesis has focused on the development of more potent AKT1 and FLT3 kinase inhibitors and on the synthesis and application of new chemical tools for the profiling of kinases involved in various types of cancers and other diseases.In this thesis, new powerful tools and assays have been developed that unite the fields of synthetic chemistry, protein biochemistry and cell biology for the global analysis of kinase expression and function. The value of chemical profiling as a method for functional proteome analysis has been further highlighted by its application as a screen to evaluate the potency and selectivity of kinase inhibitors. Show less
DNA is arguably the most important molecule found in any organism, as it contains all information to perform cellular functions and enables continuity of species. It is continuously exposed... Show more DNA is arguably the most important molecule found in any organism, as it contains all information to perform cellular functions and enables continuity of species. It is continuously exposed to DNA-damaging agents both from endogenous and exogenous sources. To protect DNA against these sources of DNA damage various DNA-repair mechanisms have evolved. If not properly repaired, DNA damage can lead to mutations that may eventually lead to cell-death or tumorigenesis. One of the most dangerous types of DNA damage is a DNA double-stranded break (DSB), in which a DNA molecule is broken into two pieces. Cells are equipped with several DSB-repair mechanisms to deal with this type of damage. Some of these mechanisms repair DSBs in an error-free fashion, while others are error-prone and can lead to the accumulation of mutations. Although accumulating many mutations in cells can lead to severely reduced cellular fitness, perfect DNA repair is less desirable in the long term as mutations allow for speciation and evolution to take place. The key question addressed in my thesis is which DSB-repair mechanisms organisms use to protect their genome against DSBs and I find alternative end-joining of DNA breaks to play a major role in maintaining genome stability. Show less
The core contributions of this thesis target the intersection of object orientation, actor model, and concurrency. We choose Java as the main target programming language and as one of the... Show more The core contributions of this thesis target the intersection of object orientation, actor model, and concurrency. We choose Java as the main target programming language and as one of the mainstream object-oriented languages. We formalize a subset of Java and its concurrency API to facilitate formal verification and reasoning about it. We create an abstract mapping from a concurrent-object modeling language, ABS, to the programming semantics of concurrent Java. We provide the formal semantics of the mapping and runtime properties of the concurrency layer including deadlines and scheduling policies. We provide an implementation of the ABS concurrency layer as a Java API library and framework utilizing the latest language additions in Java 8. Show less
A remarkable finding in recent research in psychopathology is that not every child is equally susceptible to interventions. Research showed that genetic differences, and in particular a... Show moreA remarkable finding in recent research in psychopathology is that not every child is equally susceptible to interventions. Research showed that genetic differences, and in particular a dopamine-related gene, DRD4, predict who will benefit from interventions, and who will not. In the project "What Works for Whom", this theory was tested, on a large-scale, in the field of early literacy. More than 180 schools spread over the Netherlands were involved in the experiments. We tested the hypothesis that children who were carrier of the DRD4 7-repeat allele, were more receptive to digital educational interventions; one program aimed at understanding the alphabetic principle, and the other program included digital storybooks with animated illustrations. Results for the book reading program were in line with the differential susceptibility theory. The carriers of the DRD4 7-repeat allele, about one-third of the children, benefitted extra from digital storybooks and outperformed their non-carrier peers. For non-carriers the digital books added nothing to the experience children already had with book reading in school and at home. For carriers of the DRD4 7-repeat allele the digital storybooks are a new essential in the curriculum in kindergarten. Show less
To an increasingly greater degree, incidents and crises are dominating daily life. In this context, mayors are seen as the guardian of local society. As commander-in-chief of the municipal... Show more To an increasingly greater degree, incidents and crises are dominating daily life. In this context, mayors are seen as the guardian of local society. As commander-in-chief of the municipal crisis authority, with increasing frequency they are confronted with the extremely difficult task to manage crises effectively. Mayors are expected by many to display more leadership during crises than during normal day-to-day practice. This thesis describes research into antecedents, moderators, outcomes and contingencies of effective leadership behaviour during times of crisis, paying particular attention to the performance of mayors, as heads of local authority, in the Netherlands in their role of crisis manager. What determines the success of the leadership of mayors during crises; their personality, the leadership context (its possible variations), or both? It was demonstrated that agreeableness differs in relevance for autocratic and participative leadership behaviour of the mayor. The extent to which the leadership behaviour in question is effective, was shown to also be determined by the situation. Where an autocratic line of action is sometimes inevitable—when there is high time pressure, the effectiveness of participative leadership behaviour can be connected to different team processes, especially when the crisis situation is characterised by a high level of ambiguity. Show less
