Epithelial barrier protection : implications for HIV susceptibility

The majority of HIV infections today occur through sexual HIV transmission. The female genital mucosa offers a barrier against incoming pathogens. Although, studies show that the vaginal microbiome, co-current infections and local inflammation, the use of hormonal contraceptives and microbicides, can weaken this protective lining. In this thesis in situ digital image analysis workflows were developed and used together with protein profiling, to characterize the effects of such factors on the genital mucosal barrier integrity and the immune cells therein. Topically applied microbicides can protect against HIV. In paper I we introduced image analysis as a refined tool for evaluation of microbicide safety. We confirmed that a promising microbicide candidate, Q-GRFT, had no negative effect on the rectal epithelium while causing a small, but probably biologically negligible, increase in CD4+ HIV target cells. We also discovered potential effects of multiple biopsy sampling that should be considered when designing pre-clinical studies. Specific tissue resident immune cells with an effector memory phenotype have a rapid response against re-infections and may be important against HIV infection. In paper II, we observed that HIV infected women had increased levels of CD103-CD8+ tissue resident memory cells compared to uninfected women, and that this may be due to a recent influx of these effector cells that have not yet upregulated the CD103 retention molecule. In paper III we revealed that women taking the hormonal contraceptive DMPA, had a thinner superficial layer of the female genital mucosa. Lack of this protective layer in combination with having more HIV target cells located closer to the vaginal lumen, could contribute to the increased HIV risk in women taking DMPA. In paper IV we discovered that Lactobacillus non-iners dominated women had a more intact epithelium, and Gardnerella dominated women had a different spatial localization of CD4+ cells in the epithelium. Secreted protein profiles from Lactobacillus dominant women had elevated levels of anti-inflammatory and epithelial barrier proteins compared to non-Lactobacillus dominant women. These factors may contribute to reduced HIV risk in Lactobacillus-dominant women. The results of this thesis highlight the benefits of using digital image analysis as a tool for studying spatial and structural changes in the mucosal tissue barrier and the immune cell landscape therein. We showed potential mechanisms in how different factors increase the HIV risk. These findings will support development of interventions aimed to strengthen the mucosal barrier, and thereby reduce transmission of sexually transmitted infections

Habitat selection, elevational shift, and population trend in the Norwegian population of the Eurasian Dotterel (Charadrius morinellus)

Climate change occurs at a faster rate in alpine areas and in northern latitudes compared to other regions. However, we have too little knowledge of the consequences of such changes within alpine areas. Studies regarding this subject have to our knowledge been geographically restricted, mainly to central Europe and the western hemisphere. We conducted a study in Norway during the breeding season regarding the Eurasian Dotterel (Charadrius morinellus). We counted territories, registered site variables, and used historical data to address the population trend and to uncover a potential shift in elevation. We found a significant, negative relationship between the number of territories and the density of sheep. Additionally, different levels of bedrock nutrition influenced the number of territories, where areas with intermediate bedrock richness contained the most territories. The mean elevation of a territory was 1429 m a.s.l. (range: 1221-1656 m a.s.l.) We also found that the dotterel had experienced an elevational shift in Norway from 1970 to 2022, equalling an upward shift of 17.4 m a.s.l. for each decade. If this trend continues, the loss of breeding habitat in our study sites may amount to ca 20% during the next 50 years. However, we found no significant shift in elevation for the period 2008-2022 in the same region. The population trend within our study sites was also stable from 2008 to 2022. Even though we found a stable population trend, a continued shift in the elevation will likely lead to future population declines. A potential management tool that we present here, is to limit the density of grazing sheep in alpine breeding areas. It might also be crucial for management to gather more data regarding population trends in alpine birds and the potential drivers for elevational shifts. Such data could then be used to create mitigating efforts to reduce the effects of these drivers

Effect of axillary brachial plexus blockade on baroreflex-induced skin vasomotor responses: Assessing the effectiveness of sympathetic blockade

Background: The combination of laser Doppler flowmetry and non-invasive blood pressure monitoring allows the continuous observation of cutaneous vascular resistance (CVR). Continuous recording of unmodulated skin blood flow (SBF) is very sensitive to artefacts, rendering the method unreliable. In contrast, intermittent short lasting challenges of the CVR by cardiovascular autonomic reflexes may provide information about the responsiveness of the sympathetic nervous system in the skin. Methods: Eleven patients with below-wrist hand surgery (six males and five females; aged 35.2 ± 7.1 years) performed Valsalva maneuver following axillary blockade. Skin blood flow was continuously monitored on the forearm of the side axillary blockade, as well as on the contra-lateral forearm, which was used as the control. The responses were expressed as changes compared with the baseline level derived from a resting period of 30s. The maxima

Ojämlik behandling och diskriminering inom den svenska sjukvården : en undersökning av bidragande faktorers interaktion

The Swedish health care does not live up to the objective set in the legislation about health care, that every person has the equal right to health care according to need. New reports show that both discrimination and unequal treatment among patients occur within the Swedish health care. This study is confined to include only institutions for treatment of people with physical health problems. Previous research show that people with disabilities and chronic disease, low socioeconomic status, no or few family members, and people who differs from the norm concerning gender, culture, age, sexuality etc. gets inferior treatment and care at Swedish hospitals. The aim of this study is to analyse how different factors leading to the occurrence of discrimination and unequal treatment interact with each other. This is done with a literature study combined with qualitative interviews with Swedish doctors. The method is chosen to make it possible to answer the question regarding how the main factors interact with each other and possibly find a mutual source. Other material used for this study is the Swedish legislation and a report from the Swedish discrimination ombudsman, as well as previous findings from Doctor Nina Cavalli-­‐Björkman at the University of Uppsala. The results show that discrimination and unequal treatment depend on several interacting factors joint by the fact that the Swedish healthcare system is underfinanced. The Swedish healthcare supply cannot meet the total demand, which results in discrimination and unequal treatment. Underlying norms and power structures in society result in health personnel making priorities based on deep-­‐rooted norms, which results in unequal treatment and discrimination for certain groups

Upward elevational shift of the Horned Lark (Eremophila alpestris) in alpine breeding sites at Dovrefjell, central Norway

Climate change is expected to force species to move upwards and polewards. Mountain species are at particular risk because upward elevational shifts may be limited by the maximum height of mountain ranges. The Horned Lark Eremophila alpestris breeds in the high mountains of southern Norway. Two previous studies recorded the elevation of breeding territories of Horned Larks in two regions of Dovrefjell, central Norway. In mountains around Grimsdalen (Dovre municipality) territories had a mean elevation of 1329 m (range = 1200–1450 m, n = 15) in 1969, and in mountains around Einunndalen (Folldal and Oppdal municipalities) the mean was 1339 m (range = 1240–1430 m, n = 15) in 1992. The same mountain areas were resurveyed 30–53 years later in 2022. In Grimsdalen, mean elevation of lark territories was now 1426 m (range = 1260–1570 m, n = 23) and in Einunndalen 1415 m (range = 1196–1523 m, n = 42). Overall, the data suggested a mean upward elevational shift of 2.2 m/year. The shift in elevation suggests that climate change has influenced the elevational range of the Horned Lark in the mountains of central Norway, with potential population consequences if the upward shift continues

Protein surface mimetics: understanding how ruthenium tris(bipyridines) interact with proteins.

Protein surface mimetics achieve high affinity binding by exploiting a scaffold to project binding groups over a large area of solvent exposed protein surface to make multiple co-operative non-covalent interactions. Such recognition is a pre-requisite for competitive/ orthosteric inhibition of protein-protein interactions (PPIs). This paper describes biophysical and structural studies on ruthenium(II) tris(bipyridine) surface mimetics that recognize cytochrome (cyt) c and inhibit the cyt c/ cyt c peroxidase (CCP) PPI. Binding is electrostatically driven, with enhanced affinity achieved through enthalpic contributions thought to arise from the ability of the surface mimetics to make a greater number of non-covalent interactions with surface exposed basic residues on cyt c in comparison to CCP. High field natural abundance 1H-15N HSQC NMR experiments are consistent with surface mimetics binding to cyt c in similar manner to CCP. This provides a framework for understanding recognition of proteins by supramolecular receptors and informing the design of ligands superior to the protein partners upon which they are inspired

Small molecule binding sites on the Ras:SOS complex can be exploited for inhibition of Ras activation.

Constitutively active mutant KRas displays a reduced rate of GTP hydrolysis via both intrinsic and GTPase-activating protein-catalyzed mechanisms, resulting in the perpetual activation of Ras pathways. We describe a fragment screening campaign using X-ray crystallography that led to the discovery of three fragment binding sites on the Ras:SOS complex. The identification of tool compounds binding at each of these sites allowed exploration of two new approaches to Ras pathway inhibition by stabilizing or covalently modifying the Ras:SOS complex to prevent the reloading of Ras with GTP. Initially, we identified ligands that bound reversibly to the Ras:SOS complex in two distinct sites, but these compounds were not sufficiently potent inhibitors to validate our stabilization hypothesis. We conclude by demonstrating that covalent modification of Cys118 on Ras leads to a novel mechanism of inhibition of the SOS-mediated interaction between Ras and Raf and is effective at inhibiting the exchange of labeled GDP in both mutant (G12C and G12V) and wild type Ras

Northern Crossings

This open access book uses Swedish literature and the Swedish publishing field as recurring examples todescribe and analyse the role of the literary semi-peripheral position in world literature from various perspectives and on meso, micro and macro levels, using both quantitative and qualitative methods. This includes the role of translation in the semi-periphery and the conditions under which literature travels to and from that position. The focus is not on Sweden, as such, but rather on the semi-peripheral transitional space as exemplified by the Swedish case. Consisting of three co-written chapters, this study sheds light on what might be called the semi-peripheral condition or the semi-periphery as an area of transition. As part of the Cosmopolitan and Vernacular Dynamics in World Literatures series, it makes continuous use of the concepts of 'cosmopolitan' and 'vernacular' – or rather, the processual terms, cosmopolitanization and vernacularization – which provide an overall structure to the analysis of literature and literary phenomena. In this way, the authors show that the semi-periphery is an ideal point of departure to further the understanding of world literature, because it is a place where the cosmopolitan (the literary universal) and the vernacular (the rootedness in a particular culture or place) interact in ways that have not yet been thoroughly explored. The open access edition of this book is available under a CC BY-NC-ND 3.0 licence on www.bloomsburycollections.com. Open access was funded by Riksbankens Jubileumsfond