The type-IV secretion system (T4SS) is a machinery able to transfer DNA and proteins between bacteria and in certain cases also to eukaryotic cells. This thesis compared the T4SSs present in... Show moreThe type-IV secretion system (T4SS) is a machinery able to transfer DNA and proteins between bacteria and in certain cases also to eukaryotic cells. This thesis compared the T4SSs present in Agrobacterium tumefaciens and the conjugative plasmid RP4. A. tumefaciens is able to transfer DNA into plant cells and transform them genetically. We discovered that a novel hairpin structure on the terminus of the transferred DNA allows for earlier expression of its genes in the recipient plant cell. Further, we could describe the translocation signal of the relaxase protein TraI of RP4 responsible for DNA processing and transfer via the T4SS. Additionally, it was shown that the T4SS of RP4 is able to translocate proteins from one cell to another without parallel DNA transfer. Furthermore, we were able to create a hybrid relaxase created consisting of parts from A. tumefaciens (relaxase part) and RP4 (translocation signal) that was shown to be translocated via the T4SS of RP4. Show less
When observing star-forming galaxies, we are not only seeing stellar light, but we also see how this interacts with galactic gas and dust. This thesis contains studies of the stellar, nebular and... Show moreWhen observing star-forming galaxies, we are not only seeing stellar light, but we also see how this interacts with galactic gas and dust. This thesis contains studies of the stellar, nebular and dust properties of low mass star-forming galaxies. We analyse data from the first statistical sample of low mass galaxies with stellar masses down to 10^7 solar masses, and investigate the emission from the stellar populations and their impact on and properties of the ionised surrounding gaseous nebulae, in order to understand the amount of ionising photons that are produced and the fraction of these that can escape from the galaxies. Since the stellar masses in low-mass systems may be stochastically sampled, we predict the influence of this on their nebular emission lies, and in particular on the derivation of their gas metallicity (the abundances of elements heavier than hydrogen and helium in the gas). To interpret observations of galaxies correctly, it is important to know the amount of interstellar dust grains, and its impact on the stellar and nebular light. We therefore finalise this thesis with a new method to derive dust properties in star-forming galaxies. Show less
The thesis has been an attempt to make sense of the political discourse in Kashmir from the early 1940s till the emergence of the popular uprising in the Valley towards the late 1980s. The thesis... Show moreThe thesis has been an attempt to make sense of the political discourse in Kashmir from the early 1940s till the emergence of the popular uprising in the Valley towards the late 1980s. The thesis has tried to underscore the fragmented nature of the political in Kashmir, and the implications it has had on the politics of the region, particularly on the politics of rai-shumari (self determination) and aazadi. These inner fragments or contradictions that underline the political life in Kashmir may be attributed, as the thesis has sought to argue, to the multiple political subjectivities that constitute ‘Kashmiri people’ as a community. Show less
Life expectancy is rising fast, but not all years gained are free of disease. Therefore, many people wonder to what extent the years that we have gained are enjoyable. Studies however show that... Show moreLife expectancy is rising fast, but not all years gained are free of disease. Therefore, many people wonder to what extent the years that we have gained are enjoyable. Studies however show that life satisfaction generally remains high at old age. We investigate this surprising phenomenon using data from two cross-sectional studies. We ask 1) which factors separate older people with a low from those with a high life satisfaction? And 2) how do older people maintain their high life satisfaction despite physical decline? Compared to earlier studies, this study used large and representative populations, and a broad array of objective health indicators. Physical decline was relatively unimportant for life satisfaction, especially when mental health (operationalised as depressive symptoms and experienced loneliness) remained high. Demographic variables and social resources also had no or a small relationship with life satisfaction. Only mental health was strongly associated with life satisfaction. By investigating various ways of measuring self-rated health, we show that older people may shift their norms and values in the face of declining health. This may thus explain their high life satisfaction, in spite of physical decline. Findings are discussed in relation to other literature and implications are given. Show less
This thesis demonstrates the application of bioinformatics to investigate the mechanisms that are implicated in Huntington’s Disease (HD). HD is an inherited neurodegenerative disorder and although... Show moreThis thesis demonstrates the application of bioinformatics to investigate the mechanisms that are implicated in Huntington’s Disease (HD). HD is an inherited neurodegenerative disorder and although the cause of the disease is known since 1993 we are still lacking a cure or treatment that can effectively treat the symptoms of HD. In order to tackle such a complicated case study, we followed a multidisciplinary approach to exploit the expertise and knowledge of people with diverse scientific background (chapter 2). This blend of disciplines facilitates constant collaboration between bioinformaticians, wet lab technicians, biologists, computer engineers and data scientists. A collaborative eScience model is proposed as a way to combine state-of-the-art computation analysis and laboratory work (chapter 3). At the same time, we explored methods to preserve the results, materials and methods involved in the experiment to increase the reproducibility and reusability of our research (chapter 4). In chapter 5 we identified disease signatures in blood that are functionally similar to signatures in brain. These are proposed as candidate biomarkers to be used as a monitoring tool for the state of the disease in brain, but also as a means to determine whether a treatment is successful or not. Show less
What do elections mean for a single-party regime? Can party-selected deputies do something meaningful for citizens in non-democracies? The dissertation explores how and under what conditions a... Show moreWhat do elections mean for a single-party regime? Can party-selected deputies do something meaningful for citizens in non-democracies? The dissertation explores how and under what conditions a single-party authoritarian regime instrumentalizes popularly elected congress to strengthen its rule in local society. It takes contemporary China as an empirical focus for this exploration. Instead of perceiving Chinese congress either simply as authoritarian window dressing or as an immediate catalyst for democratization, this research is devoted to examining the motivations, strategies, and behaviors of the party regime in playing the cards of congressional elections and representation to make its rule more robust and resilient. This project mainly adopts comparative case study methods, with some quantitative data serving as supportive statistical evidence. As a whole, my thesis argues that congressional election and post-election representation are two cards of China’s party regime. By strategically downplaying input electoral competition but promoting output congressional representation, the communist regime has been striving to develop a mass-line democracy as an alternative to liberal democracy, which features the “Leninist trinity” of the Party’s leadership, the rule of law, and people’s democracy, as well as a new brand of mobilized representation relying on the accountability from the top down. Show less
'What is the desire of the medium?' is both a rhetorical question and a fundamental one. The rhetorical question serves as a framework for investigating the interplay between the artist/designer... Show more'What is the desire of the medium?' is both a rhetorical question and a fundamental one. The rhetorical question serves as a framework for investigating the interplay between the artist/designer and the medium during the creative act. Arts and design operate on the level of problematising: they do not reproduce the visible, they make visible. By this, I am suggesting that there is no preconceived objective criterion: all perception needs to be produced. A critical supposition is that the complexity of the world cannot be reduced to either macro- or micro-systems or models (anti-representation). The only interesting route to pursue is to investigate what a medium does (asignification), not what it is (essentialism). My interest lies in affective capacities, not inherent properties and their respective place in any taxonomy or ontological setting. This requires the exploration of a non-hierarchical, flat ontology based on the equality of all parties (human and nonhuman). I propose four backgrounds against which to investigate the desire of the medium: ethoscape (which deals with affect), ideoscape (which deals with concepts), mediascape (forms of expression) and technoscape (forms of content). The desire of the medium is located somewhere in the middle between affect, concept, expression and content. Show less
Dit proefschrift beschrijft orgaan schade tijdens coronaire bypass operaties (coronary artery bypass surgery; CABG). Orgaan schade wordt deels veroorzaakt door de operatie technieken en kan in... Show moreDit proefschrift beschrijft orgaan schade tijdens coronaire bypass operaties (coronary artery bypass surgery; CABG). Orgaan schade wordt deels veroorzaakt door de operatie technieken en kan in belangrijke mate de klinische resultaten be_nvloeden. Met name voor de oudere comorbide pati_nt kan orgaan schade invloed hebben op het herstel proces en het uiteindelijke resultaat. Middels geselecteerde biomarker bepalingen in bloed en urine (retrospectieve -en prospectief gerandomiseerde studies) , beschrijft dit proefschrift globale -en orgaan specifieke schade tijdens drie verschillende operatie technieken, te weten; Mini-closed Circuit CABG (MCABG), off-pump CABG, een techniek zonder gebruik making van een hartlong machine (OPCAB) en de zogenaamde conventionele on-pump CABG (CCABG). OPCAB en MCABG zijn twee betrekkelijk nieuwe en innovatie technieken. De uitkomsten van de in dit proefschrift verzamelde studies geven aan dat deze twee technieken met minder orgaan schade gepaard gaan. In de discussie van dit proefschrift worden de verkregen resultaten besproken en gerelateerd aan uitkomsten van recent verschenen grote outcome studies betreffende de behandeling van coronaria lijden. Een voorstel wordt geformuleerd hoe deze laatste inzichten op een nuttige wijze in praktijk gebracht kunnen worden. Naar aanleiding van de bestudeerde orgaan schade tijdens de genoemde behandel strategie_n in dit proefschrift lijkt het alsof vocht beperkende strategie_n zoals tijdens MCABG een gunstig effect hebben op peri-operatieve orgaan schade en klinische uitkomsten. Toekomstige studies kunnen dit fenomeen verder verduidelijken. Show less
Venous thrombosis is a disease that occurs in 1-2 per 1000 people per year. At the time of their first venous thrombosis, approximately 50% of women are exposed to reproductive risk factors (oral... Show moreVenous thrombosis is a disease that occurs in 1-2 per 1000 people per year. At the time of their first venous thrombosis, approximately 50% of women are exposed to reproductive risk factors (oral contraception, postmenopausal hormone therapy, pregnancy and the puerperium). In this thesis, we showed that these women are at particularly high risk of venous thrombosis if they have previously experienced an episode of superficial vein thrombosis, or are over the age of 50 years (Chapters 2 and 3). There is no known male counterpart to female reproductive risk factors. Nevertheless, the incidence of venous thrombosis is approximately similar in men and women. In this thesis we established that, once female reproductive risk factors are taken into account, men have an approximately twofold higher risk of both first and recurrent venous thrombosis than women (Chapters 4 and 5). Further to these findings, in Chapter 6, we reviewed the literature on sex-specific risk factors for venous thrombosis. We hypothesized that sex-specific genetic risk factors, an excess in overweight and smoking, or hypercoagulable changes such as microalbuminuria may explain the higher risk of venous thrombosis in men than in women. Show less
The study addresses and explains the issue of negative descriptions of the Arab Other in modern Iranian thought. It attempts to understand and illustrate what the notion of the Arab means for... Show moreThe study addresses and explains the issue of negative descriptions of the Arab Other in modern Iranian thought. It attempts to understand and illustrate what the notion of the Arab means for Iranians and how Arabs are portrayed and by examining how they depicted, It describes why they depicted in modern time in such a way, linking this portrayal to a range of ideologies in modern Iran. In doing this research, the researcher has limited his analysis to a certain body of fiction and non-fiction texts. he has selected writings produced by prominent Iranian authors of a variety of ideological affiliations, including literary works such as short stories, novels, historical stories and works published in academic or semi-academic journals, as well as some works in the field of historiography, all of which were written in Persian by Iranian writers between the 1850s and the 1950s. In a broader sense, the study offers an analytical model for the understanding of the Iranian notions of Self and Other in the nineteenth and twentieth centuries. It investigates the ethnic and racial attitudes of a number of Iranian writers and thinkers toward Arabs, contributing to an understanding of the way in which the Iranian identity has been shaped in modern times. Show less
Deze dissertatie brengt de werkwijze in kaart van de Delftse bestuurscolleges, eind zeventiende eeuw. Dat waren er drie: - De vier burgemeesters vormden het dagelijks bestuur: zij beslisten over... Show moreDeze dissertatie brengt de werkwijze in kaart van de Delftse bestuurscolleges, eind zeventiende eeuw. Dat waren er drie: - De vier burgemeesters vormden het dagelijks bestuur: zij beslisten over alle uitgaven van de stad, deden veel benoemingen en onderhielden contacten met bijvoorbeeld andere steden en het landsbestuur. - Het college van schout, burgemeesters en schepenen, oftewel de heren van de wet, stelde de wetten en regels vast in Delft, en besloot ook over de toepassing ervan. Grofweg de helft van de onderwerpen die bij de heren van de wet ter tafel kwamen, waren aangedragen door de stadsbewoners in de vorm verzoekschriften. - De veertigraad bemoeide zich vooral met het bestuur van heel Holland; de stad had daarin ook daadwerkelijk een stem. Daarnaast had de raad een belangrijke rol bij de jaarlijkse verkiezing van de heren van de wet, evenals van andere bestuurders. Vaak deden de Delftse stadsbestuurders onderzoek voordat zij een besluit namen. Zij informeerden bij betrokkenen, onderzochten hoe hun voorgangers in vergelijkbare gevallen hadden besloten of welke regels andere steden op hetzelfde punt hadden ingesteld. Als het onderwerp ingewikkeld was, benoemden zij een commissie om het onderzoek uit te voeren. seventeenth century, Dutch Republic, City government, magistracy, burgomasters, city council, council of forty, petition, committee, policy Show less
Motor disturbances, cognitive decline and psychiatric symptoms are considered as the key symptoms of Huntington__s disease (HD). Yet, other prevalent features include unintended weight loss, sleep... Show moreMotor disturbances, cognitive decline and psychiatric symptoms are considered as the key symptoms of Huntington__s disease (HD). Yet, other prevalent features include unintended weight loss, sleep and circadian disturbances and autonomic nervous system dysfunction. The nature of these features supports a pivotal role of the hypothalamus in the HD disease process. In this thesis data is presented from immunocytochemical and in situ hybridization studies demonstrating substantial pathology in hypothalamic neuropeptide expression in HD patients. Main findings include neuropeptide changes in the suprachiasmatic nucleus, the body__s master clock, that will likely be responsible for disruption of 24h circadian rhythmicity. Secondly, the neuronal histaminergic system is hyperactive at both the level of the hypothalamic tuberomamillary nucleus as well as in the cerebral neocortex. These changes could partly explain weight loss and cognitive decline in patients. The expression of neuropeptides in the hypothalamic paraventricular and infundibular nuclei, however, seems to be relatively unaffected by the HD disease process. Finally, a discrepancy between mRNA expression and protein expression of many hypothalamic neuropeptides was observed that can be partly explained by a decrease of prohormone convertase expression. Interestingly, hypothalamic changes in existing HD transgenic rodent models are largely non-representative of hypothalamic changes in HD patients. Show less
This thesis describes the pathophysiology of insulin resistance in the South Asian population and comprises studies on pharmacological and weight loss interventions in insulin resistant patients.... Show moreThis thesis describes the pathophysiology of insulin resistance in the South Asian population and comprises studies on pharmacological and weight loss interventions in insulin resistant patients. Because of the increasing number of patients with obesity and T2DM, more research is needed to identify patients at risk of developing T2DM and to elucidate specific therapeutic targets to improve insulin resistance. For now, the prevention of overweight and obesity is the most essential step in the fight against the worldwide obesity and T2DM epidemic Show less
The main underlying mechanism resulting in cardiovascular complications is the formation of atherosclerotic lesions in arteries. The progression of the lesion is hallmarked by a chronic... Show moreThe main underlying mechanism resulting in cardiovascular complications is the formation of atherosclerotic lesions in arteries. The progression of the lesion is hallmarked by a chronic inflammatory immune response in the arterial wall. Activated T helper cells differentiate into subsets, each producing a specific set of cytokines. T helper cell subsets contribute to the formation of the lesions, with a pro-atherogenic role for T helper 1 and a protective role for regulatory T cells. Cytokines of the IL-12 family play a crucial role in de differentiation of T helper cells. In this thesis I studied the role of IL-12 family members IL-27, IL-30 and IL-35 in atherosclerotic lesion formation. Furthermore the contribution of IL-37, part of the IL-1 family, was studied. In addition to modifications in lesion size and composition, I focus on the effects of the cytokines on T cell activation and differentiation. Show less
Implantable cardioverter defibrillators (ICDs) have become an important treatment op- tion for both patients who survived ventricular arrhythmia and patients with cardiac heart disease at risk for... Show moreImplantable cardioverter defibrillators (ICDs) have become an important treatment op- tion for both patients who survived ventricular arrhythmia and patients with cardiac heart disease at risk for ventricular arrhythmias. The aim of the current thesis is to study ICD patients outside the setting of a clinical trial and compare the findings with evi- dence of routine clinical trials. The thesis is divided in 3 parts: in Part I the long-term follow-up of ICD patients is studied, in Part II the safety of ICD treatment __ including implantation-related complications __ is assessed, and in Part III a patient tailored evalu- ation was conducted to assess which patient characteristics are associated with benefit from ICD treatment. Show less
The general objective of this thesis was to investigate new (quantitative) MR techniques and MR markers in the light of both AD and cerebral aging. The quantitative MR techniques that we used were... Show moreThe general objective of this thesis was to investigate new (quantitative) MR techniques and MR markers in the light of both AD and cerebral aging. The quantitative MR techniques that we used were MTI, tCBF and WSS measurements. The new markers we studied were cerebral microbleeds and iron accumulation in the basal ganglia. In chapter 2 we investigated whether MTI changes could be detected in the GM, WM or both in patients suffering from MCI or AD. Using MTI we found evidence for structural brain changes in both GM and WM of patients with MCI and AD. Furthermore, these MTI changes were related to cognitive impairment as expressed by the mini mental state examination (MMSE) score. These findings imply that cerebral changes can be detected in both GM and WM even before patients are clinically demented. The finding of MTI changes in the GM might relate to classical AD type pathology, whereas WM MTI changes could indicate concomitant vascular pathology. The findings in chapter 2 raised the question of how the MTI changes found in this study are distributed over the GM and WM. This was investigated in chapter 3. In this study we showed that brain damage, as detected by MTI, is widespread over the lobes in both AD and MCI patients whereas GM damage is more focally present in the temporal and frontal lobe of MCI patients. These findings are compatible with the knowledge that GM damage originates from the temporal lobe in AD. This interpretation is further supported by the observed independent association between temporal GM peak height and cognitive decline. MTI changes were found in all four lobes of the MCI patients investigated in this study and show the involvement of a diffuse process affecting the WM even before patients are clinically demented, a finding potentially explained by the presence of diffuse vascular pathology. Chapter 4 shows that the tCBF is strongly associated with parenchymal volume rather than age and, although much weaker, with the severity of WMHs. Although the association between tCBF and parenchyma volume seems straightforward, this finding has important implications for future studies. Volume flow measurements should be corrected for parenchymal volume ratherthan age in all future studies in which flow measurements are being used as a diagnostic tool. In addition, studies including elderly patients or patients with a pathological increase of WMHs, such as diabetic type II subjects, should also correct their tCBF measurements for WMH volumes. Chapter 5 shows that hemodynamic conditions of the carotid and basilar arteries, as expressed in lower WSS parameters, are worse in both MCI and AD compared to controls. In addition, the WSS parameters were found to correlate strongly with cognition. Again, this study is additional evidence for an important role of vascular pathology in the development of AD. In chapter 6, we found a high prevalence of microbleeds in a population of patients suffering from vascular disease or at high risk of developing this condition. Age, hypertension and WMH were the most important risk factors for microbleeds, especially when located in the cortico-subcortical junction and basal ganglia. Regarding the associations between the presence and location of microbleeds on the one hand and parameters of cognitive functioning on the other, chapter 7 shows that microbleeds located infratentorially are associated with impaired cognitive functioning in the aging population with increased vascular risk factors. This suggests that in elderly individuals microbleeds in the posterior fossa should be considered a sign of small vessel disease with potential functional consequences. The semi-quantative scale for scoring basal ganglia hypo-intensity on T2*- weighted imaging presented in chapter 8 was associated with markers of neurodegeneration. This study showed that low signal intensity of the caudate nucleus T2*-weighted MR is a frequent finding which is associated with more cerebral atrophy, a higher load of WMH and a higher load of invisible changes in both cortical GM and NAWM non-demented elderly. Furthermore, hypo- intensity limited to the globus pallidus and putamen was not associated with any of these parameters of neurodegeneration. In chapter 9 we present a method for automated detection and classification of hypo-intense regions on T2-weighted MR images of the basal ganglia. In this chapter we not only show an association between basal ganglia hypo-intensity and cardiovascular risk factors but also with measures of cognitive functioning. From this we conclude that hypo-intensity of the basal ganglia on T2-weighted MR is not only a radiological finding accompanying cerebral aging but also an independent marker of neurodegeneration. Show less
Rheumatoid Arthritis (RA) is a chronic autoimmune disorder that affects approximately 0.5-1% of the population. RA leads to inflammation of the joints and leads to irreversible destruction of... Show moreRheumatoid Arthritis (RA) is a chronic autoimmune disorder that affects approximately 0.5-1% of the population. RA leads to inflammation of the joints and leads to irreversible destruction of joints with subsequently to significant morbidity, disability for patients. Remarkably the amount of joint destruction differs substantially between patients. Currently medication mainly aims at diminishing inflammation. Because joint destruction seems to develop even when the inflammation level is low, since RA is still not curable and finally because joint destruction is irreversible, joint destruction becomes an increasingly important feature in patients with RA. In this dissertation, different aspects of joint destruction in RA were investigated. To highlight the most important findings: first of all the heritability of joint destruction was demonstrated. In addition several genes were further studied. Two genetic findings were of most interest: IL2RA was associated with joint destruction. Since there is already medication available that aims at IL2RA, this finding creates a new treatment option for the nearby future. More intriguingly, SPAG16, an thus far with sperm association gene, appears to be relevant in joint destruction in RA as well. This put a totally new light on the gene. Naturally, most of the newly discovered associations will need further research before they can be applied in clinical practice. Show less
Quality of care- and of surgical oncology in particular- is gaining momentum. In this thesis the scientific bases of minimal volume standards and quality indicators are evaluated. Also the impact... Show moreQuality of care- and of surgical oncology in particular- is gaining momentum. In this thesis the scientific bases of minimal volume standards and quality indicators are evaluated. Also the impact of centralization of pancreatic surgery is investigated as is the influence of comorbidity on patient outcomes after colorectal surgery Show less
Stars near massive black holes move on elliptical orbits which precess slowly, exerting persistent gravitational torques on each other. In this the- sis we present four important consequences of... Show moreStars near massive black holes move on elliptical orbits which precess slowly, exerting persistent gravitational torques on each other. In this the- sis we present four important consequences of these gravitational torques: 1) A new instability which exposes the inherently unstable nature of ec- centric stellar disks in galactic nuclei, 2) A density depression of stars near massive black holes due to enhanced angular momentum relaxation and tidal disruptions, 3) A signature of high-eccentricity orbits for stars formed by Hills__ mechanism at large radii from the massive black hole, and a directly-observable statistic that can highlight these populations, and 4) A new dynamical process which we call "secular dynamical anti-friction" which boosts the orbital eccentricity of hypothesized intermediate-mass black holes as they spiral into massive black holes Show less
