1,569 research outputs found
Characterizing determinants of BK Polyomavirus-specific immune response
No full textBK polyomavirus (BKPyV) is one of now 13 human polyomavirus (HPyV) species detected in humans. BKPyV is only known to infect humans and seroprevalence rates of more than 90% have been reported in adult populations around the world. Following primary infection, BKPyV persists in the renourinary tract without causing any disease as evidenced by urinary shedding in 5% - 10% of healthy immunocompetent blood donors.
In immunocompromised persons, however, BKPyV can cause significant diseases whereby uncontrolled high-level replication may lead to organ invasive pathologies in kidneys, bladder, lungs, vasculature, and the central nervous system. The most consistently found diseases are BKPyV-associated hemorrhagic cystitis (BKPyVHC) in 5%-20% allogeneic hematopoietic stem cells transplant patients, and BKPyV-associated nephropathy (BKPyVAN) in 1%-15% of kidney transplant patients. BKPyVHC is highly symptomatic with pain, anemic bleeding, and increased mortality. BKPyVAN is asymptomatic except for progressive renal failure and premature return to dialysis. Both entities are characterized by high-level viral replication i.e. with urine BKPyV loads of 8-10 log10 Geq/mL, plasma BKPyV loads often above 4 log10 Geq/mL, and an allogeneic constellation between the virus-infected host cell and the available T-cell effectors. Despite these similarities, the clinical manifestations are strikingly different suggesting relevant, but experimentally undefined differences in pathogenesis. Thus, BKPyVHC typically occurs within 4 weeks after allogeneic HSCT and is confined to the bladder, and typically without kidney involvement. By contrast, BKPyVAN is diagnosed around 3-6 months after kidney transplantation and confined to the kidney allograft without causing cystitis. Although high-level BKPyV replication should be formally amenable to antiviral drug treatment, no effective and BKPyV-specific antiviral therapy is currently available. Therefore, a better understanding of the immune alteration in both diseases has been deemed essential to identify patients at risk and to develop prophylactic, preemptive and therapeutic strategies.
The currently recommended strategy for BKPyVAN is to screen kidney transplant patients for BKPyV replication and to promptly reduce immunosuppressive therapy in those with significant replication to facilitate mounting of BKPyV-specific T cell responses and thereby preventing progression to disease. This manoeuver has been linked to expanding BKPyV-specific T cell responses in the peripheral blood of kidney transplant patients. However, this approach may place patients at risk for acute rejection episodes that predispose equally well to premature kidney transplant failure. Although the clinical feasibility of reducing immunosuppression and curtailing BKPyV replication has been shown to be effective in prospective cohort studies for many, but not all of kidney transplant patients, this approach has not been possible in allogeneic HSCT patients because of concurrent or imminent graft-versus host disease. Thus, there are significant gaps in the current understanding of the BKPyV– host interaction in the normal host and in the allogeneic setting, which need to be investigated for a more effective and safer management of these significant viral complications.
In this thesis, the interaction of BKPyV and the immune response has been approached from two different angles. In the first project, potential mechanisms of BKPyV immune evasion were studied. Here, we focused on a small accessory protein called agnoprotein encoded as a leader protein in the late viral early region (LVGR). Although HPyV genomes overall show a very similar genome organization, agnoproteins are only found in the genomes of BKPyV and JCPyV that have a kidney tropisms, but not in any of the other 11 presumably non-renotropic HPyVs. We hypothesized that agnoprotein could play a role in immune evasion by downregulating HLA expression. The effects of agnoprotein were studied on HLA class I and II expression in vitro by flow cytometry following transfection of primary human renal tubular epithelial cells, which are the viral target of BKPyV-associated nephropathy. In addition, transfected human UTA-6 cells were studied as well as UTA-6 cells bearing a tetracycline-regulated agnoprotein. As control, the effects were compared with the ICP47 protein of Herpes simplex virus-1, which has been previously reported to effectively down-regulate HLA class I. Although both viral proteins share some similarities at the protein level, our results showed that BKPyV agnoprotein did not down-regulate HLA class I or class II molecules. Also, there was not inhibitory effect on the increase of HLA-class I or class-II surface expression following exposure to interferon-. By contrast, ICP47 reduced HLA class I surface expression, but not class II. We also evaluated effects of agnoprotein on virus epitope-specific T-cell killing by 51Chromium release assay, however no interference could be observed. We concluded that agnoprotein did not contribute to these types of HLA-dependent immune evasion processes. However, further investigations are needed to understand if agnoprotein could contribute to viral immune escape by other mechanisms.
In the second project, we aimed at better characterizing BKPyV-specific CD8 T cell immunity targeting epitopes encoded in the early viral gene region (EVGR). Selected coding sequences of the BKPyV EVGR were submitted to two web-based computer algorithms (SYFPEITHI, IEDB) in order to predict immunodominant 9mer epitopes presented by 14 frequent HLA-class I molecules. For an experimental confirmation, 97 different 9mer epitopes were chemically synthesized and tested in 42 healthy individuals. A total of 39 epitopes could be confirmed by interferon- ELISpot assay in at least 30% of healthy individuals. Interestingly, most of the 9mer epitopes appeared to cluster in short amino acid stretches, and some 9mer could be presented by more than one HLA class I allele as expected for immunodominant domains. HLA-specific presentation was demonstrated by 9mer- MHC-I streptamers for 21/39 (54%) epitopes. The 9mer dependent T-cell killing by 51Chromium release assay and the CD107a surface detection indicated that the 9mer epitopes could be recognized by cytotoxic T-cells. Moving to a clinically relevant situation, 13 9mer epitopes could be validated in 19 kidney transplant patients protected from, or recovering from, BKPyV viremia. The results suggest that, pending further corroboration in larger patient populations, novel 9mer epitopes can be identified, which are associated with CD8 T cell control of BKPyV replication. Thus the identified immunodominant 9mer T-cell epitopes could be further developed for clinical assays to better predict the risk and the recovery of BKPyV diseases, help guiding immunosuppression reduction, and to develop specific adoptive T-cell therapy or vaccine responses to prevent or treat BKPyV-associated disease
The origin of redshift in Brillouin spectra of silica films containing tin nanoparticles
No full textHousing Policy and Housing Finance in the Czech Republic during Transition: An Example of the Schism between the Still-Living Past and the Need of Reform
No full textThis book contains the description and evaluation of a profound housing system reform constituting part of the transition from a centrally planned to a market economy in the Czech Republic. It addresses two goals: to evaluate housing subsidies (reforms) by application of improved methods of welfare economics and, secondly, to list the main factors explaining the particular outcomes of selected reforms. The author applied methods of welfare economics for an evaluation of housing subsidies in a scale unique in housing studies. The analysis of underlying factors influencing formation of housing reforms brought new findings about the essence of transition in post-socialist countries
Knowledge-based Design: Developing urban & regional design into a science
No full textThe assumptions underlying this book are that urban & regional design can be developed into a societally relevant science, that this depends on the view held regarding the significance of urban & regional design to society, and what is considered to be the object of the discipline derived from this view. The author bases these assumptions on the knowledge and insights she has acquired during the last fifteen years; the first ten years within the Chair of Urban & Regional Design, and after that within the Chair of Spatial Planning, both of the Faculty of Architecture of the Delft University of Technology
Adapting Land Administration to the Institutional Framework of Customary Tenure: The Case of Peri-Urban Ghana
No full textHistorical experience in many Sub-Saharan African countries demonstrates that an alternative approach to conventional land administration methods is required to appropriately secure tenure and administer land rights in customary areas. This book is about dealing with the dynamics of customary tenure and with land governance and institutional capacity issues necessary to implement land administration at the local level. Methods for implementing land administration systems at the local level have been presented in a three-phased tenure model. The author concludes that customary tenure institutions have their own mechanisms for adapting to societal change, and a desirable solution would therefore be to adapt land administration to the institutional framework of customary tenure. The information in this book will be essential for academic work in land administration in developing countries. It will prove a useful reference for policy makers and practitioners in the land administration field
Environmental Impacts During the Operational Phase of Residential Buildings
No full textTo date, the focus in the field of sustainable building has been on new building design. However, existing residential buildings inflict great environmental burden through three causes: continuous energy consumption, regular building maintenance and replacements.
This publication analyses and compares these three causes of environmental burden and shows that material resources needed for replacements generally have a limited potential to reduce environmental impact. Reducing energy consumption for climate control and electrical appliances is much more effective. According to the author, sustainable measures should be tested for shifts in the kind of environmental impact caused due to the use of alternative types of energy resources and altered material quantities. The sustainability of the electricity supply is essential to decrease the total environmental impact of the residential building stock
Urban informality shaped by labor: Addressing the spatial logics of favelas
No full textThis doctoral thesis presents the results of ten years of research on informal settlements, with particular reference to Brazilian favelas. The research aimed to understand the social dynamics of the production of space in these settlements. To this purpose, the author took residence in favelas and performed field research for a total of six years, including the witnessing of a resettlement process from a favela to a formal social housing development in the city of Maceií³, in Brazil. The social dynamics that produces and influences the space of the favelas observed in the field were systematically codified in a new pedagogic tool by the author. As main findings from the analysis, it emerged that labor primarily shapes, plans and governs space in informal settlements. Working activities explain the emergence of these settlements, influence the dynamics of space inside the domain of the house, influence the shape of streets up to the margin of the favelas, but also has influence on city and global scales. From the residents’ perspective, labor represents both a means to earn their subsistence, livelihoods and underscores their inner self-esteem as human beings. Working practices originally present in the favelas were in fact restored in the social housing development to where citizens were relocated, with their original domestic function. According to this thesis, labor practices of inhabitants of informal settlements must be addressed when designing housing solutions for deprived citizens fighting for their survival and must be considered as a housing right. The reasons why the current housing approaches do not contemplate work are understood in context and interpreted according to their historic and economic backgrounds. A housing architectural and planning approach aimed at restoring the combination of working and domestic functions of human beings is proposed instead
On Measuring and Explaining Neighbourhood Success: A Behavioural Economic Approach
No full textThis study combines qualitative and quantitative research methods to explain which factors contribute to a problem-free or problematic functioning of neighbourhoods in general and especially of Dutch neighbourhoods that were built in the first years after World War II. An important part of the book is about the development of measuring instruments. Special attention is given to the development of a risk scale that offers researchers and policymakers the opportunity to distinguish on a metric level between problematic and successful neighbourhoods.
This book brings together key insights from Urban Studies and central elements of Behavioural Game Theory. The author applies the notions of strong reciprocity and altruistic punishment in Prisoner’s Dilemmas and Assurance Games to describe and explain the interdependent choices that residents make when they act as producers and maintainers of the social climate in the daily living environment of a problem-free early post-Second World War neighbourhood.
 
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