| 1. |
- Sheng, Nongfei, 1988-
(författare)
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Revisiting dental caries as an immunodeficiency disorder
- 2023
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Worldwide, dental caries is the major human chronic disease, with billions of people affected in terms of life quality impairment and high society costs that consumes 5-10% of the global healthcare budget. In Western countries dental caries has declined dramatically, with a trajectory of 15% high-risk individuals with recurrent caries and a non-responder behavior to standard prevention. This dissertation work focuses on revisiting the primary causes of caries development by exploring human and Streptococcus mutans genetic variation in a prospective case-control sample of 452 Swedish adolescents followed from 12 and 17 years of age.Genetic variation of PRH1 and PRH2, encoding acidic proline-rich protein receptors for indigenous oral streptococci and actinomycetes, specified high (P4a), moderate (P6) and low (P1) caries phenotypes of different risk and causal profiles (Paper I). Susceptible individuals thus classified into the immunodeficiency caries type (P4a) or the lifestyle caries type (P1) that accounted for naturally resistant individuals. Orthodontic treatment during adolescence exerted a further negative load that resulted in an even bigger difference in caries progression between P4a and P1 individuals. Importantly, immunodeficiency P4a individuals were identified as risk individuals at the clinic and therefore given extra fluoride.Adhesin gene variation in S. mutans specified SpaP A/B/C and Cnm/Cbm adhesion types that matched individual caries progression (Paper II). The saliva/DMBT1 binding avidity of high cariogenicity SpaP and Cnm but not of low cariogenicity SpaP A types correlated positively with the caries activity of the individual strain donor. SpaP-guided MLST typing also revealed SpaP A/B/C biotypes with high SpaP B and low SpaP A cariogenicity lineages that besides adhesion differed in acid production and acid tolerance properties. The SpaP A/B/C receptor-binding V-regions had markedly different structures. In paper III, we found unstable residency of a mixed and fluctuating SpaP A/B/C adhesion mode, a high cariogenicity SpaP B-1 subtype and Cnm adhesin expression and glycosylation to contribute to mono-microbial caries progression in naturally resistant low caries P1 phenotypes. By, contrast, moderate- and high-caries P6 and P4a phenotypes contributed to poly- and meta-microbial caries progression. In addition, the S. mutans adhesion types showed specificity (tropism) for individual hosts and plausible family distribution patterns.DMBT1 protein size isoforms I-III predicted caries progression but differently in the PRH1/PRH2 genetic background and influenced the infection profile of S. mutans adhesion and virulence types (Paper IV). Caries progression increased as DMBT1 isoform size decreased in the order of isoform I > II > III, suggesting that loss of the large isoform III glycotype may impair immunity. The finding that DMBT1 isoform variation did not add predictive power to the P4a+ but to P4a- phenotypes allowed a novel sick and health classification system.In conclusion, PRH1, PRH2 may represent a pattern recognition and immunity pathway for tooth homeostasis and formation of the indigenous flora on teeth. It can predict prospective caries risk and might be implemented in caries prevention based on genetic risk and cause at the clinical level. DMBT1 appears as an evolutionary different but intertwined immunity pathway for surveillance of infectious agents in general at teeth and mucosal surfaces. The S. mutans organism is heterogenous with biotypes and lineages that match individual caries development. Narrowing both S. mutans and PRH1, PRH2 phenotypes suggest a mono- (P1), poly- (P6) and even meta- (P4a) microbial characters of dental caries.
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| 2. |
- Levy, Joshua, 1990-
(författare)
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Homeless in 'The People's Home' : Exploring the experiences of 'vulnerable EU citizens' in Stockholm, Sweden
- 2022
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Since the early 2010s, Stockholm has seen a visible emergence of homelessness and begging amongst predominantly Romanian citizens, many of whom identify as Roma, who have collectively come to be known as ‘vulnerable EU citizens’. Despite their prolonged presence and a great deal of political attention, there remains a lack of in-depth research into their experiences of homelessness in the city. This thesis addresses this gap and seeks to forge a deeper understanding for both the experiences and spatial practices of these individuals in Stockholm, as well as the responses with which they have been met by state and society at the local and national levels. The study employs a mixture of qualitative research methods, primarily grounded in semi-structured interviews with ‘vulnerable EU citizens’ in Stockholm, alongside interviews with other actors in the city, ethnographic observations and text analysis. It is theoretically grounded primarily within the critical literature on geographies of homelessness.The thesis consists of a comprehensive summary and three papers, all with a focus on understanding the experiences of ‘vulnerable EU citizens’ in Stockholm and the ambivalent responses with which they have been met. Paper 1 explores issues relating to access to water and sanitation infrastructure for this group in Stockholm. In doing so it reveals the multiple strategies that individuals must employ in order to meet their basic needs, as well as the effects that limited access can have with regard to their emotional experiences and spatial practices in the city. Paper 2 directs attention to the use of public space for livelihood activities in two areas of Stockholm, with a focus on the ways in which local police have responded to begging practices. It demonstrates the ways in which unevenly punitive policing landscapes have developed through interwoven relations including the agency of individual police officers and the path-dependencies created by local spatial orders. Paper 3 turns to analyse the logics and effects of national political discourses addressing the presence of ‘vulnerable EU citizens’ in Sweden, placing these political discourses into conversation with interview material collected in Stockholm with ‘vulnerable EU citizens’ themselves. The analysis suggests a political response that is sensitive to the potentially damaging effects that this visible form of homelessness can have from the perspective of the majority housed-population, more so than to the needs of those actually experiencing homelessness. Together, the papers highlight the multiple barriers that these individuals must overcome in order to meet their basic needs, while suggesting that the ambivalence of state responses stems from a need to maintain a discursive moral legitimacy while seeking to promote the ‘voluntary return’ of these individuals to their countries of origin. These results then suggest a conflation of homelessness management with a politics of international mobility control, and the thesis contributes to the international literature on geographies of homelessness by engaging with this under researched aspect of modern homelessness management in the European context.
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| 3. |
- Magnusson, Karin, 1981-
(författare)
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Poly-and oligothiophenes : Optical probes for multimodal fluorescent assessment of biological processes
- 2015
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- One interesting class of molecules in the research field of imaging biological processes is luminescent conjugated polythiophenes, LCPs. These fluorescent probes have a flexible backbone consisting of repetitive thiophene units. Due to this backbone, the probes possess unique abilities to give rise to different spectral signatures depending on their target and environment. LCPs are a polydispersed material meaning there is an uneven distribution of lengths of the probe. Recently, monodispersed chemically well-defined material denoted luminescent conjugated oligothiophenes, LCOs, with an exact number of repetitive units and distinct sidechain functionalities along the backbone has been developed. LCOs have the advantages of being smaller which leads to higher ability to cross the blood brain barrier. The synthesis of minor chemical alterations is also more simplified due to the well-defined materials.During my doctoral studies I have used both LCPs and LCOs to study biological processes such as conformational variation of protein aggregates in prion diseases and cellular uptake in normal cells and cancer cells. The research has generally been based on the probes capability to emit light upon irradiation and the interaction with their targets has mainly been assessed through variations in fluorescence intensity, emission-and excitation profiles and fluorescence lifetime decay. These studies verified the utility of LCPs and LCOs for staining and discrimination of both prion strains and cell phenotypes. The results also demonstrated the pronounced influence minor chemical modifications have on the LCO´s staining capacity.
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| 4. |
- Gideonsson, Pär, 1982-
(författare)
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Helicobacter pylori : molecular insights into regulation of adhesion properties
- 2016
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Helicobacter pylori infects the human stomach and triggers an inflammatory response that damages the gastric tissue. This host-pathogen interplay has dire consequences as up to 20 % of infected individuals develop peptic ulcer disease or gastric cancer. Given that half of the world’s population is infected, the number of afflicted humans is staggering and also tells that H. pylori is extremely efficient in spreading and maintaining infection. To enable persistent infection many factors play a role, but one important feature of H. pylori is its impressive ability to adhere to the slimy gastric mucus layer and the underlying epithelial cells. This occurs mainly via the BabA and SabA proteins that bind ABO/Leb- and sLex/sLea-antigens. I have in my thesis studied how these two proteins are utilized and regulated.H. pylori transcription is in part controlled by two-component systems (TCSs) that use a sensor protein and a DNA-binding response regulator. We have studied how these systems control sabA and to some extent babA and indeed found a better map of how sabA and babA is regulated at the transcriptional level. We also found that variations in a polynucleotide T-tract located in the sabA promotor could fine-tune SabA expression/ sLex-binding. Thus we have exposed how strict regulation by TCSs combined with stochastic processes together shapes attachment in the bacterial population.As the buffering mucus layer is constantly exfoliated, placing H. pylori in bactericidal acid, we hypothesized that low pH should abrogate adhesion. SabA expression was indeed repressed in low pH, however BabA expression remained unaffected. The BabA/ Leb-binding was instead directly reversibly hampered by low pH and the degree of pH sensitivity was strain dependent and encoded in the BabA sequence. We believe that the pH dependent loss of binding is one key factor H. pylori utilizes to maintain persistent infection.BabA is divided in generalists that bind ABO antigens and specialists that only bind blood group (bg) O. We co-crystalized BabA bound to these receptors and established the structural basis for generalist vs. specialist discrimination. We furthermore found a disulfide-clasped loop (CL2) in the center of the binding domain crucial for binding. Breaking CL2 with N-Acetylcysteine (NAC) disrupted binding and H. pylori infection mice experiments revealed inflammatory reduction upon NAC-treatment.In sum, I have in my thesis dissected how H. pylori controls its adhesive abilities and how intrinsic properties in binding can be exploited for therapeutic purposes.
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| 5. |
- Henriksson, Sara, 1981-
(författare)
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Helicobacter pylori : multitalented adaptation of binding properties
- 2012
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Helicobacter pylori infects and persistently colonizes the stomach, which results in gastritis and in some individuals peptic ulcer disease or gastric cancer. Adherence of H. pylori to the epithelium is an important factor for development of disease. Attachment is mediated by the adhesins BabA and SabA that binds the ABO/Leb blood group antigens and sialylated glycoconjugates respectively. High-affinity attachment could be anticipated to be of disadvantage for H. pylori because epithelial cells have a fast turnover rate and the dislocated and shed epithelial cells would carry attached bacteria to the acidic gastric juice in the lumen. However, here we describe that H. pylori manage to adapt to this innate clearance mechanism by unique acid regulatory binding properties of its adhesins. We propose that pH regulated binding properties enable bacteria to detachment from host cells for chemotactic guided motility and successful return to the more neutral epithelium for a fresh restart of the infectious cycle. By comparison of BabA from different stomach loci we identified amino acid key position for acid regulated binding activity.Previous studies found lower prevalence of Leb-binding among H. pylori isolates from southern Europe compared to Sweden. Here we tested if the reduced prevalence of Leb-binding could be explained by a novel binding mode; in among Spanish strains, we identified S812 that demonstrates preference for multivalent binding to ABO antigens in glycolipids; we found that 812 BabA had drifted in its preferred binding epitope away from the consensus a1,2fucosylation and towards the blood group A and B derivatives. Such epitope drift might in particular optimize binding to ABO antigens in densely packed lipid rafts.In parallel, we studied the influence of BabA for disease progression by an inventory of gastric biopsies. BabA correlated both with the oncoprotein CagA, the VacAs1 toxin and, in addition, to severe disease progression. We further correlate BabA expression with positive secretor phenotype and stronger adhesion of H. pylori in vitro.For functional adherence studies in vitro, we constructed a recombinant Leb-expressing cell lineage that supports BabA mediated H. pylori attachment.
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| 7. |
- Borén, Thomas, Professor, 1967-, et al.
(författare)
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Special issue : Urban contestations
- 2023
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Ingår i: Journal of Urban Affairs. - : Informa UK Limited. - 0735-2166 .- 1467-9906. ; 45:1, s. 1-1
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)
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| 8. |
- Rofougaran, Reza, 1978-
(författare)
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DNA precursor biosynthesis-allosteric regulation and medical applications
- 2008
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Ribonucleotide reductase (RNR) is a key enzyme for de novo dNTP biosynthesis. We have studied nucleotide-dependent oligomerization of the allosterically regulated mammalian RNR using a mass spectrometry–related technique called Gas-phase Electrophoretic Mobility Macromolecule Analysis (GEMMA). Our results showed that dATP and ATP induce the formation of an α6β2 protein complex. This complex can either be active or inactive depending on whether ATP or dATP is bound.In order to understand whether formation of the large complexes is a general feature in the class Ia RNRs, we compared the mammalian RNR to the E. coli enzyme. The E. coli protein is regarded a prototype for all class Ia RNRs. We found that the E. coli RNR cycles between an active α2β2 form (in the presence of ATP, dTTP or dGTP) and an inactive α4β4 form in the presence of dATP or a combination of ATP with dTTP/dGTP. The E. coli R1 mutant (H59A) which needs higher dATP concentrations to be inhibited than the wild-type enzyme had decreased ability to form these complexes. It remains to be discovered how the regulation functions in the mammalian enzyme where both the active and inactive forms are α6β2 complexes.An alternative way to produce dNTPs is via salvage biosynthesis where deoxyribonucleosides are taken up from outside the cell and phosphorylated by deoxyribonucleoside kinases. We have found that the pathogen Trypanosoma brucei, which causes African sleeping sickness, has a very efficient salvage of adenosine, deoxyadenosine and adenosine analogs such as adenine arabinoside (Ara-A). One of the conclusions made was that this nucleoside analog is phosphorylated by the T. brucei adenosine kinase and kills the parasite by causing nucleotide pool imbalances and by incorporation into nucleic acids. Ara-A-based therapies can hopefully be developed into new medicines against African sleeping sickness.Generally, the dNTPs produced from the de novo and salvage pathways can be imported into mitochondria and participate in mtDNA replication. The minimal mtDNA replisome contains DNA polymerase γA, DNA polymerase γB, helicase (TWINKLE) and the mitochondrial single-stranded DNA-binding protein (mtSSB). Here, it was demonstrated that the primase-related domain (N-terminal region) of the TWINKLE protein lacked primase activity and instead contributes to single-stranded DNA binding and DNA helicase activities. This region is not absolutely required for mitochondrial DNA replisome function but is needed for the formation of long DNA products.
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| 9. |
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