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  • Disputation: 2024-04-18 13:00 MIT.A.121, Umeå
    Devinney, Hannah
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för datavetenskap. Umeå universitet, Samhällsvetenskapliga fakulteten, Umeå centrum för genusstudier (UCGS).
    Gender and representation: investigations of bias in natural language processing2024Doktorsavhandling, monografi (Övrigt vetenskapligt)
    Abstract [sv]

    Nuförtiden möter vi dagligen språkteknologi i olika former. Ibland är det tydligt för oss att detta sker, till exempel när vi använder maskinöversättning. Andra gånger är det svårare att upptäcka, som när sociala medier rekommenderar oss inlägg. Språkteknologi ligger också till grund för större AI-system, som till exempel kan användas för att bevilja eller avslå låneansökningar och därmed ha stora materiella effekter på våra liv. I takt med att ChatGPT och andra stora språkmodeller blir mer populära kommer vi också att konfronteras med fler och fler maskingenererade texter.       

    Maskininlärningsmetoder, som de flesta av dessa verktyg förlitar sig på idag, upprepar mönster de 'ser' i sin träningsdata. Vanligtvis är detta språkdata som människor har skrivit eller talat, så förutom saker som meningsstruktur innehåller den också information om hur vi konstruerar vårt samhälle. Detta inkluderar även stereotyper och andra fördomar. Vi kallar dessa mönster för 'social bias' och de upprepas, eller till och med förvärras, av maskininlärningssystem. När språkteknologi blir en del av vårt språkliga sammanhang blir de också delaktiga i att föra vidare stereotyper genom att till exempel anta att sjuksköterskor är kvinnor och läkare män, eller systematiskt föreslå män framför kvinnor för befordran. Tekniken blir därmed ett verktyg som samhället använder för att bygga upp makt -- och maktskillnader -- genom att sprida och normalisera orättvisa idéer samt genom att bidra till orättvisa resursfördelningar.       

    Den här avhandlingen utforskar sociala fördomar om kön och genus, inkludering av trans- och ickebinära personer samt queer representation i språkteknologier genom en feministisk och intersektionell lins. Tre frågor ställs: Hur tänker forskare på och mäter 'genus' när de undersöker 'genusbias' i språkteknologi? Vilka könsstereotyper finns i data som används för att träna språkteknologiska modeller? Hur representeras queera (särskilt trans- och ickebinära) människor, kroppar och erfarenheter i produktionen av dessa teknologier? Avhandlingen finner att ickebinära personer osynliggörs av fördomar i såväl modeller som data, men också av forskare som vill ta itu med könsfördomar. Män och kvinnor reduceras till cisheteronormativa roller och stereotyper, med litet utrymme att vara en individ bortom kön. Vi kan mildra några av dessa problem, till exempel genom att lägga till mer ickebinärt språk i träningsdatan, men fullständiga lösningar är svåra att uppnå på grund av det komplexa samspelet mellan samhälle och teknik. Dessutom måste vi förbli flexibla, eftersom vår förståelse av samhället, stereotyper och 'bias' i sig skiftar över tid och med sammanhanget.

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  • Disputation: 2024-04-19 09:00 Hörsal B, byggnad 1D, 9 trappor, Umeå
    Behzadi, Arvin
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Neurovetenskaper.
    Biomarkers for diagnosis and prognosis in amyotrophic lateral sclerosis2024Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
    Abstract [en]

    Background: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder characterized by loss of upper and lower motor neurons, leading to paresis, muscle atrophy, and respiratory failure. ALS can be difficult to diagnose and prognosticate early.

    Aim: To investigate the diagnostic and prognostic characteristics of biomarkers in cerebrospinal fluid (CSF), plasma, and skeletal muscle tissue in patients with ALS.

    Paper I: Neurofilament light chain (NFL) and phosphorylated neurofilament heavy chain (pNFH) were analyzed in CSF using enzyme-linked immunosorbent assay (ELISA), and NFL in plasma was analyzed using single-molecule array (SIMOA). CSF NFL, CSF pNFH, and plasma NFL concentrations can differentiate ALS patients from ALS mimics, and were significantly negatively correlated with the disease duration in ALS patients.

    Paper II: Myosin heavy chain (MyHC) isoforms in extraocular muscles were investigated using immunofluorescence. Control donors had significantly higher proportion of myofibers containing MyHCIIa and significantly lower proportion of myofibers containing MyHCeom in the global layer compared to spinal-onset ALS and bulbar-onset ALS donors. Disease duration in the spinal-onset ALS donors was significantly correlated with the proportion of myofibers containing MyHCIIa in the global layer and MyHCeom in the orbital layer.

    Paper III: The study combined the neurofilament concentrations from Paper I, with cytokines previously analyzed in CSF and plasma using SIMOA, to investigate distinct molecular phenotypes in ALS. Patients with bulbar-onset ALS had significantly higher concentrations of CSF tumor necrosis factor α (TNF-α) compared to ALS mimics. TNF-α and NFL were significantly correlated with each other in both CSF and plasma in ALS patients. Combined analysis of NFL and IL-6 in plasma identified molecular prognostic subgroups in ALS patients.

    Paper IV: Creatine kinase (CK), high-sensitivity cardiac troponin T (hs-cTnT), hs-cTnI, and cystatin C (CysC) were analyzed in plasma in a fully accredited laboratory. CK and hs-cTnT concentrations were significantly elevated in limb-onset ALS compared to controls and bulbar-onset ALS. hs-cTnT concentrations were significantly elevated in truncal-onset ALS compared to controls and bulbar-onset ALS. Multivariable Cox proportional hazards models indicated elevated concentrations of CysC as a significant marker for worse prognosis in ALS.

    Conclusions: The papers report diagnostic and prognostic characteristics of biomarkers in CSF, plasma, and muscle tissue in ALS patients. The significant findings for biomarkers in plasma could be of value since plasma sampling does not involve a lumbar puncture.

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  • Disputation: 2024-04-19 09:00 Major Groove, Umeå
    Gilmore, Michael C.
    Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten).
    Studies on cell wall recycling and modification in Gram-negative bacteria2024Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
    Abstract [en]

    The bacterial cell wall is made from peptidoglycan (PG), a heteropolymer which forms a bag-like exoskeleton that envelopes the cell. PG is constantly remodelled during growth and division, and in response to environmental stimuli. Decades of study of this process have focused largely on a select few model organisms, leaving its diversity poorly understood. In this thesis, I present studies on different aspects of PG recycling and modification in several Gram-negative models, with a particular focus on the plant pathogen Agrobacterium tumefaciens, a model of the Hyphomicrobiales group of the Alphaproteobacteria which includes several species of medical and environmental interest. It is shown that A. tumefaciens encodes a novel PG transporter, which is vital for cell wall integrity and resistance to β- lactam antibiotics, and widely conserved in the Hyphomicrobiales and Rhodobacterales orders. Growth defects caused by the loss of the transporter are suppressed by mutations in a novel glycopolymer, which is hypothesized to play a role in sequestering metal ions and thereby lowering periplasmic oxidative stress. Next, in collaboration, it is shown that PG recycling in the best studied model, Escherichia coli, is more complicated than previously thought. Rather than depending mostly on the MFS-family transporter AmpG, E. coli uses an ABC transporter, MppA-OppBCDF or AmpG depending on the growth phase and conditions. Finally, two studies on modification of PG by deacetylation are presented. First, A. tumefaciens is shown to encode a novel anhydroMurNAc deacetylase, which specifically deacetylates the PG chain termini. Then, it is shown that the causative agent of Legionnaires’ disease, Legionella pneumophila, depends on deacetylation of its PG during infection for defence against host lysozyme and correct polar placement of its type IV secretion system. 

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  • Disputation: 2024-04-19 09:00 Lilla Hörsalen, KBE301, KBC-huset, Umeå
    Golosovskaia, Elena
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Development of in silico methods to aid chemical risk assessment: focusing on kinetic interactions in mixtures2024Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
    Abstract [en]

    The environment and biota are constantly exposed to numerous chemicals through contaminated food, soil, water, and air. These chemicals can be taken up and distributed to reach sensitive tissues where they may cause various effects. Many of these chemicals lack data on their environmental and human health effects. Traditional toxicological tests relying on animal experiments are today being phased out in favor of cell-based and computational methods for early hazard detection and exposure assessment. This thesis focuses on developing computational tools for various stages of chemical risk assessment with a particular focus on bisphenols and per- and polyfluoroalkyl substances (PFAS). In Paper I, quantitative structure-activity relationship (QSAR) models covering molecular targets of the thyroid hormone (TH) system were developed and applied to two data sets to prioritize chemicals of concern for detailed toxicological studies. In Papers II and III, experimental and computational approaches were combined to study toxicokinetics and maternal transfer in zebrafish. Our main focus was to study potential mixture effects on administration, distribution, metabolism, and elimination (ADME) processes, i.e., to reveal if co-exposed chemicals impact each other’s ADME. Physiologically based kinetic (PBK) mixture models were developed to allow translation of external exposure concentrations into tissue concentrations and modelling plausible mechanisms of chemical interactions in a mixture.

    Main findings of this thesis are summarized as follows:

    • Application of QSAR models (Paper I) to two chemical inventories revealed that chemicals found in human blood could induce a large iirange of pathways in the TH system whereas chemicals used in Sweden with predicted high exposure index to consumers showed a lower likelihood to induce TH pathways.

    • Two zebrafish experiments (Paper II and Paper III) did not reveal statistically significant mixture effects on ADME of chemicals.

    • In Paper II, a PBK mixture model for PFAS accounting for competitive plasma protein binding was developed. The model demonstrated good predictive performance. Competitive plasma protein binding did not affect the predicted internal concentrations.

    • In Paper III we developed a binary PBK model parametrized for two bisphenols and PFOS showing that competitive plasma protein binding has an effect on ADME of bisphenols at PFOS concentrations at μg/L levels. At these levels internal concentrations of bisphenols were shown to decrease, implying that PFOS outcompeted bisphenols from studied plasma proteins resulting in higher excretion rates.

    Developed QSAR models showed good predictive power and the ability to identify and prioritize chemicals of concern with confidence. Additionally, PBK models aid in hypotheses testing and predicting exposure concentrations at which co-exposed chemicals could potentially influence each other’s ADME properties. These tools will provide overall early tier data on exposure and effects using non-testing methods in assessment of risks of chemicals. 

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  • Disputation: 2024-04-19 10:00 Hörsal UB.A.220, Samhällsvetarhuset, Umeå
    Kjellgren, Maria
    Umeå universitet, Samhällsvetenskapliga fakulteten, Institutionen för socialt arbete.
    Skolkuratorns samtalspraktik: en studie om individuella samtal med barn i den svenska grundskolan2024Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
    Abstract [sv]

    Denna avhandling fyller en del av den kunskapslucka som finns gällande skolkuratorers individuella samtalspraktik. Det övergripande syftet är att undersöka den individuella samtals praktik som skolkurator bedriver i den svenska kommunala grundskolan, inom ramen för skolans elevhälsoarbete. Tre grundläggande forskningsfrågor formulerades enligt följande: Vad kännetecknar det skolsociala arbetet med avseende på struktur, process och interventioner i skolkuratorns individuella samtal med barn? Hur beskriver skolkuratorer sina erfarenheter av hjälpande och försvårande aspekter i skolsocialt arbete, interventioner och utförande samt samverkan med andra aktörer i elevhälsoteamet? Vad kännetecknar skolkuratorns individuella samtal utifrån ungdomarnas erfarenheter och uttryckta behov?

    Avhandlingen består av fyra delstudier vilka publicerats i vetenskapliga artiklar. Den ena studien koncentrerar sig på skolkuratorernas egna erfarenheter av individuella samtal med barn, baserad på fokusgruppsintervjuer som genomfördes med 22 skolkuratorer (fördelade på fyra fokusgrupper). I den andra studien beskrev samma grupp av skolkuratorer sina erfarenheter av att vara en del av ett multiprofessionellt team, elevhälsoteamet (EHT) under fokusgruppsintervjuerna. Dessa två studier analyserades genom innehållsanalys. Den tredje studien i avhandlingen består av en kvantitativ protokollstudie avseende barns karakteristika, samtalsstrategier och interventioner. Skolkuratorer (20 stycken) fyllde i ett protokoll efter avslutat samtal med ett barn. Totalt samlades 193 protokoll in baserade på samma antal unika barn och analyserades med deskriptiv statistik. Den fjärde studiens syfte var att fördjupa kunskapen om de individuella skolkurativa samtalen ur ungdomarnas perspektiv. Individuella intervjuer med ungdomar (15 år) genomfördes och analyserades sedan genom innehållsanalys.

    Avhandlingen belyser nödvändigheten för barn att uttrycka sig själva, när det gäller sin livssituation, sin oro och sina problem. Avhandlingen visar att skolkurator kan vara en aktör för att hjälpa och avlasta barn genom individuella samtal. Skolkuratorer beskrivs som skolans och elevhälsoteamets (EHT) psykosociala expert, med fördjupad kunskap om psykosociala effekter och konsekvenser för barn.

    En ytterligare slutsats i avhandlingen är att det saknas regler eller riktlinjer för skolkuratorns individuella samtal i svenska grundskolor. Det kan vara av vikt att sådana regler och riktlinjer upprättas, för att säkerställa att barn blir lyssnade och för att kunna uttrycka sin berättelse i en trygg och tillitsfull samtalsmiljö i skolan.

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  • Disputation: 2024-04-26 09:00 Umeälven, byggnad 28, Umeå
    Ekbäck, Erik
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Barn- och ungdomspsykiatri.
    Depression in teenagers and young adults: foundational studies of the new treatment paradigm TARA: Training for Awareness, Resilience, and Action2024Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
    Abstract [en]

    Introduction: Depression in adolescents and young adults is an increasing global health concern and available treatments are not convincingly effective. It is therefore important to develop and test novel treatments to improve treatment outcomes. This dissertation lays the foundation for the evaluation of a Swedish version of the treatment program Training for Awareness, Resilience, and Action (TARA), and tests the psychometric properties of the primary outcome measure for that evaluation.

    Objectives: This dissertation aims to 1. Translate and pilot test TARA in Swedish medical students, 2. Evaluate the psychometric properties of the Swedish version of the Reynolds Adolescent Depression Scale second edition (RADS-2) in a clinical sample, 3. Perform a single arm multicenter clinical pilot study of the feasibility and safety of TARA and 4. Design a randomized controlled trial to test the clinical effectiveness of TARA.

    Methods: The TARA manual was translated into Swedish and 23 self-selected medical students, with or without mental disorders, received TARA. Self-rating as well as qualitative evaluation was performed. Patients (N = 536 individuals) with a variety of psychiatric diagnoses completed RADS-2 and other questionnaires for psychometric evaluation of RADS- 2. Thirty-five adolescents and young adults with depression received TARA either face-to-face or online, with data collection before, during, and after the treatment. The study design and statistical analysis plan for the randomized controlled trial was conceived and developed.

    Results: It was feasible and acceptable to give TARA to Swedish medical students and they described the program as an uncommon meeting ground for personal empowerment. Support was found for the four-factor structure of RADS-2, and the scale demonstrated good validity and acceptable to good reliability. The clinical pilot study further supported the feasibility and clinical safety of TARA, and preliminary signs of effectiveness were seen. A detailed description of the pragmatic, multicenter, randomized controlled superiority trial that will evaluate the clinical effectiveness of TARA compared to standard treatment for depression was outlined, peer reviewed, and published in a study protocol with a statistical analysis plan.

    Conclusions: The present results indicate that TARA is feasible and safe in Swedish clinical and non-clinical contexts. RADS-2 is a suitable outcome measure to use in routine clinical practice as well as in the present and future trials of depression. The initiated randomized controlled trial will be an important next step logically following the studies and results presented in this dissertation.

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  • Disputation: 2024-04-26 09:00 Stora Hörsalen, KBC byggnad KBE303
    Knyazeva, Anastasia
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Non-canonical ATG8 conjugation in ESCRT-driven membrane remodeling processes2024Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
    Abstract [en]

    ATG8 family proteins have the unique ability to conjugate to membrane lipids. Initially identified as a hallmark of autophagy, ATG8 lipidation is emerging as an important regulator of a growing list of non-degradative cellular functions. In this thesis we developed and applied novel chemical genetic approaches to perturb dynamic membrane remodeling processes and induce non-canonical ATG8 conjugation in cells. We investigated novel roles of ATG8 in membrane deformation processes carried out by the Endosomal Sorting Complex Requiredfor Transport (ESCRT) machinery.

    In Paper I, using a high-throughput phenotypic screening assay, we developed a collection of pseudo-natural product-based compounds which potently induce ATG8 lipidation in mammalian cells. The most potent compound, Tantalosin, induces ATG8 lipidation which is insensitive to simultaneous inhibition of autophagosome-lysosome fusion, suggesting a non-canonical function ofTantalosin-induced ATG8 conjugation.

    In Paper II we investigated the molecular target of Tantalosin. We found that Tantalosin targets the ESCRT-III protein IST1 and inhibits IST1-CHMP1B copolymer formation. This inhibition results in the impairment of transferrin receptor (TfR) recycling resulting in the rapid accumulation of the receptor inearly/sorting endosomes. At the same time, Tantalosin induces non-canonical ATG8 conjugation on stalled sorting endosomes containing TfR. This conjugation is dependent on the ATG16L1-ATG5-ATG12 complex which is recruited to stalled endosomes via ATG16L1-V-ATPase interaction.

    In Paper III and Paper IV we studied the induction of non-canonical ATG8 lipidation in response to endolysosomal membrane damage. We used two established membrane damaging agents: V. Cholerae cytotoxin MakA and the lysosomotropic compound, LLOMe. In Paper III we demonstrated that, at lowpH, MakA assembles into small pores in endosomal membranes which arerecognized by the ESCRT membrane repair machinery. Non-canonical ATG8 lipidation in response to MakA-induced pore formation is mediated by V-ATPase activity. In Paper IV we identified a novel player in the lysosomal damage response – TECRP1. TECPR1 is recruited to damaged membranes where it forms an alternative ATG16L1-independent E3 ligase complex with the ATG5-ATG12 conjugate and plays a role in the restoration of lysosomal integrity after damage.

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  • Disputation: 2024-04-26 09:00 UB A.240, Lindellhallen 4, Umeå
    Höglund, Per
    Umeå universitet, Samhällsvetenskapliga fakulteten, Institutionen för psykologi.
    Stress, sleep disturbance, and related ill-health: from prevalence and risk-factors to indicated interventions2024Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
    Abstract [en]

    With focus on stress-related ill-health and insomnia/sleep disturbance, the overall aim of this thesis was to determine severity and prevalence, risk factors and effectiveness of low-intensity group sessions. This was accomplished by taking epidemiological and quasi-experimental approaches. 

    With the aim of examining symptom severity and prevalence of insomnia, burnout, anxiety, depression, and somatization across different age groups and sexes, Study I used cross-sectional data (n=3406) from the baseline data collection of the Västerbotten Environmental Health Study (VEHS). In comparison to men, women in most age groups exhibited higher levels of symptom severity and prevalence of caseness in various mental health conditions. Insomnia (28.6%) and burnout (17.3%) were common in the population.

    With focus on risk factors for insomnia and burnout, Study II used a longitudinal design and VEHS data (n=1702–1972) to compare a range of mental and somatic conditions in a general population. The results showed that all examined health conditions were risk factors for cases of insomnia and burnout. For example, insomnia can increase the risk of developing burnout (odds ratio: 2.67), and burnout increase the risk of developing insomnia (odds ratio: 2.73), underscoring the importance of early detection and prevention. 

    The aim of Study III was to examine the effectiveness of four low-intensity group sessions for stress (n=274) and sleep disturbance (n=106) conducted by psychology students. A non-randomized controlled trial design was used in primary care with naturally occurring groups. A control group (n=221) was recruited via social media. Whereas effects were small at post-treatment, a substantial proportion of the patients showed a reliable improvement or recovery at 3-month follow-up. 

    This thesis provides support for the assumption that severity and prevalence of insomnia, burnout, anxiety, depression, and somatization are common in the population. Burnout and insomnia are mutual risk factors and underscore the importance of indicated prevention in primary care. Low-intensity group interventions facilitated by non-experts can be effective and scalable for patients with stress and sleep disturbance.

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  • Disputation: 2024-04-26 09:00 Sal D, 9 trappor, Norrlands Universitetssjukhus, Umeå
    Lundström, Anna
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap.
    Autonomic cardiac control in long QT syndrome: clinical studies of arrhythmogenic triggers2024Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
    Abstract [en]

    Background: Long QT syndrome (LQTS) is an inherited cardiac disease characterized by prolonged cardiac repolarization and an increased risk for life-threatening arrhythmias. These arrhythmias are typically triggered by adrenergic stimuli, such as physical activity and intense emotions, implicating that the sympathetic part of the autonomic nervous system (ANS) is involved in arrhythmogenesis. However, symptoms also commonly occur swimming and diving, situations associated with dual activation of both branches of the ANS. This observation suggests that both sympathetic and parasympathetic physiological responses may contribute to the initiation of arrhythmias in individuals with LQTS.

    Aim: The overall aim of this thesis was to describe the cardiac autonomic response in LQTS patients during daily activities, exercise, and swimming, as well as to assess the presence of arrhythmias during activities in water. 

    Methods: In all 4 studies electrocardiograms (ECGs) were recorded. In study I and II, a 24-hour ECG (Holter) system was used. In study III and IV, a waterproof 2-lead ECG device (Actiwave-Cardio) was used. In study I, ECGs were collected from adult LQTS patients (n = 44) and healthy controls (n = 44) during a submaximal bicycle exercise stress test. In study II, annual 24-hour ECG recordings (n = 575) during ordinary daily living was retrospectively collected in children with LQTS (n = 116). In study III, children with LQTS type 1 (LQT1) (n = 15) and age and sex matched healthy controls (n = 15) performed face immersion (FI), swimming, diving, and whole-body submersion (WBS). In study IV, healthy adolescents aged 15 years performed FI (n = 54) and ice-water immersion (IWI) of the body (n = 20).

    Heart rate responses and spectral analysis of heart rate variability (HRV) were assessed. HRV measures the beat-to-beat variation of the RR intervals of the heart, making it possible to non-invasively analyze the cardiac autonomic influence on the heart. The total power (PTOT) reflects all the variation during the recorded period. The high frequency (HF) component reflects parasympathetic activity, while the low frequency (LF) is influenced by both the sympathetic and parasympathetic activity.

    Results: In study I, LQTS patients had a decreased heart rate reduction and a lower PTOT, LF and HF than controls during the post-exercise phase. LQTS patients off beta-blocker (BB) treatment showed a lower HF and higher LF/HF ratio compared to LQTS patients on BB treatment. In study II, a correlation between heart rate and changes in HRV parameters was observed. At higher heart rates, the whole cohort of LQTS patients, as well as the subgroup of LQTS patients off BB, had lower HRV values than controls. A pattern was observed indicating that LQT1 patients had lower HF in the age group of 1-10 years, with this trend shifting as age increased, resulting in lower HF in the LQT2 patients aged 15-18 years. LQT1 girls aged 10-18 years had lower PTOT than LQT1 boys. Study III showed that LQT1 patients had a smaller reduction in heart rate during FI and WBS than controls. LQT1 patients had a lower HRV before, during and after FI and WBS than controls. In study IV, in healthy adolescents, supraventricular extrasystoles were relatively common during both FI and IWI, and 2 of 54 had ventricular bigeminy during FI. FI resulted in a more pronounced heart rate reduction compared to IWI.

    Conclusions: The results of these studies indicate that individuals with LQTS have an aberrant cardiac response to activities that affects the ANS. After exercise and in response to water activities, the parasympathetic effect on both the heart rate and HRV appears depressed in LQTS patients. Additionally, during everyday activities, LQTS patients generally have lower HRV values at higher heart rates compared to controls. These findings suggest that both branches of the ANS might be involved in arrhythmogenesis in this patient group, and that an increased understanding of the ANS role could improve patient management and treatment. 

    The results from the ice-water study indicate that the ventricular arrhythmia risk is likely higher during whole-body submersion with apnea. The absence of arrhythmias in beta-blocked LQT1 patients indicates effective protection by their current treatment.

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  • Disputation: 2024-04-26 09:00 Universitetsledningshuset (ULED), Triple Helix, Umeå
    Shimanda, Panduleni Penipawa
    Umeå universitet, Medicinska fakulteten, Institutionen för epidemiologi och global hälsa.
    Rheumatic heart disease in Namibia: evaluating the burden and the cost-effectiveness of a preventive strategy2024Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
    Abstract [en]

    Background: Rheumatic Heart Disease (RHD) is a neglected public health problem, which is most prevalent in low-and middle-income countries. It affects over 460 million people and causes about 390,000 deaths annually, predominantly children, young adults, and women. This thesis aimed to assess the burden of Rheumatic Heart Disease in Namibia and to evaluate the cost-effectiveness of a preventive strategy.

    Methods: Data was obtained from primary and secondary sources in four distinct studies. The first study analysed the RHD outpatient and inpatient data from 2010-2020. The second employed a cross-sectional survey, incorporating a questionnaire with the EQ-5D-5L tool, to assess the health-related quality of life and healthcare usage pre- and post-RHD diagnosis. A systematic review was conducted in the third study synthesising preventive interventions, while the fourth study used a Markov model to evaluate the cost-effectiveness of a secondary prevention strategy in Namibia.

    Results: The clinical RHD prevalence was estimated at 28 per 100,000 cases. From the survey, 83 RHD patients participated, predominantly women (77%) and primarily young adults aged 20-29 (41%). The majority (84%) had received surgical treatment. Notably, there was a significant increase in mean QALY from 0.773 pre-diagnosis to 0.941 post-diagnosis (p<0.001). The systematic review underscored the effectiveness of school and nurse-led prevention programmes. The health economic evaluation demonstrated that echocardiographic RHD screening was cost-effective, with an Incremental Cost-Effectiveness Ratio of N$ 28,516.75 per QALY gained, which falls below Namibia’s GDP per capita.

    Conclusions: The findings highlight a significant gap in RHD data, particularly in high-endemic regions like Sub-Saharan Africa, emphasising the need for enhanced data quality and surveillance. The effectiveness of school-based and community-led programmes is apparent, but the scarcity of data from diverse regions limits a comprehensive understanding of optimal prevention strategies. Echocardiographic screening is identified as a feasible component of RHD secondary prevention in Africa, pointing towards a policy need for improved surveillance and data quality. Future research should investigate the impact of various interventions on RHD incidence and prevalence.

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  • Disputation: 2024-04-26 13:00 Hörsal Betula, byggnad 6M, Umeå
    Löwenmark, Thyra
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Gut microbiota in colorectal cancer: The importance of Parvimonas micra2024Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
    Abstract [en]

    Colorectal cancer (CRC) is a heterogenous disease consisting of multiple molecular subtypes, each of which has diverse treatment responses and prognoses. The importance of the gut microbiota in CRC development and progression has undergone increasing recognition in recent years, with a structural segregation in terms of microbial composition between CRC patients and healthy controls. However, many questions remain before a full understanding of the impact of the gut microbiota on CRC is reached. The overall aim of this thesis was to explore the role of gut microbes in CRC, including their potential as CRC biomarkers and associations with clinicopathological, immunological, and molecular traits of CRC. A particular focus was the CRC-associated oral pathogen Parvimonas micra.

    To investigate faecal microbiota as a potential biomarker for CRC, we studied the presence of specific bacteria in faeces from CRC patients and controls using qPCR. We found higher levels of P. micra in faecal samples from CRC patients than from control patients. A test for high levels of P. micra was able to identify CRC with a specificity of 87.3% and a sensitivity of 60.5%. Adding the oral pathogen Fusobacterium nucleatum, colibactin-producing bacteria, and faecal haemoglobin to the test enhanced its sensitivity.

    We further aimed to explore the associations of P. micra and F. nucleatum with molecular subtypes of CRC and the tumour immune response. The levels of P. micra and F. nucleatum, as analysed by qPCR in both faeces and tumour tissue from CRC patients, were found to be positively correlated. High levels of intratumoural P. micra and F. nucleatum were associated with tumours of the microsatellite instable subtype and BRAF-mutated tumours. For F. nucleatum, an additional association with right-sided tumours was found. Moreover, both P. micra and F. nucleatum in tumour tissue were associated with the immune-activated consensus molecular subtype (CMS) 1 subtype of CRC. In line with this finding, we found novel associations between intratumoural P. micra and specific immune traits, which were evaluated by flow cytometry, indicating an active immune response in CRC. These results were further confirmed using transcriptomics. However, no associations with specific immune traits were found for F. nucleatum.

    We also investigated associations between faecal and intratumoural levels of P. micra and F. nucleatum and survival in CRC patients. CRC patients with high levels of intratumoural P. micra and F. nucleatum showed reduced five-year cancer-specific survival. This association remained significant for P. micra in multivariable analysis. No associations with cancer-specific survival were found for levels of P. micra and F. nucleatum in faeces.

    To investigate the faecal microbial landscape of CRC patients on a larger scale, we used 16S rRNA sequencing. Network analysis revealed a cluster of associated bacteria, including P. micra and F. nucleatum, as well as other CRC-related pathogens such as Bacteroides fragilis, Peptostreptococcus stomatitis, and Porphyromonas spp. Furthermore, beta-diversity analysis indicated a significantly different gut microbial composition depending on tumour location and microsatellite instability status. Interestingly, three of the six annotated species most strongly associated with microsatellite instable tumours were also present in the cluster: P. micra, F. nucleatum, and P. stomatis.

    In conclusion, our results suggest P. micra as a putative candidate for a future non-invasive microbial test panel for detection of CRC. Moreover, our results indicate that intratumoural P. micra and F. nucleatum are associated with immune-active subtypes of CRC, including microsatellite instable tumours and tumours of the CMS1 subtype, as well as decreased patient survival. Furthermore, P. micra and F. nucleatum were found to be associated with a cluster of other CRC-related oral pathogens. An improved understanding of the role of the gut microbiota in tumour progression may lead to the identification of important biomarkers for CRC disease and outcome, as well as potential targets for future therapy.

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  • Disputation: 2024-04-26 13:00 Hörsal NAT.D.410, Umeå
    Lundkvist, Moa J.
    Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten).
    Towards forecasting epigenetic repression2024Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
    Abstract [en]

    Multicellular organisms form many different cell types from one genome, which requires differential gene activity. The Polycomb system upholds the correct gene expression programs by epigenetically silencing genes that encode critical transcription regulators. It is defined by the protein complexes Polycomb Repressive Complexes 1 and 2 (PRC1 and PRC2). PRC2 methylates lysine 27 on histone H3 (H3K27) on nucleosomes. This is necessary for the repression, but it is not known why. In Drosophila melanogaster both PRC1 and PRC2 bind to DNA elements called PREs near the target genes. In human cells, PRC2 are tethered to CpG islands, but PRC1 tethering is not well understood. In paper I of the thesis we uncover the first comprehensive catalogue of DNA elements, Polycomb Tethering Elements (PTEs), that target PRC1 to human developmental genes. PTEs and CpG islands may be intermixed—forming a PRE equivalent—or offset from each other. Genes equipped with PTEs have low transcription and are stochastically reactivated upon deletion of their PTE. In paper II, we used a computational model to stochastically simulate both the random and targeted methylation by PRC2, to understand the dynamics of H3K27 methylation. The model was constrained by data, such as the levels of methylation in cells, allosteric stimulation of PRC2 by H3K27 trimethylation, and the differing catalytic efficiency of each successive methyl transfer to H3K27. We used it to investigate PRC2’s allosteric stimulation, the relationship between the rates of methylation and demethylation and cell cycle length, and how the rapid embryonic development of D. melanogaster affects the maternal contribution of H3K27me3 to the embryo. In paper III we used polymer modelling to investigate how chromatin folding by PRC1-H3K27me3 interactions affects contacts inside loci repressed by the Polycomb system. With these three studies, this thesis combines experimental and computational methods to further our understanding of epigenetic repression by the Polycomb system.

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  • Disputation: 2024-04-26 13:15 Hörsal SAM.A.280, Samhällsvetarhuset, Umeå
    Karlsson Bazarschi, Johanna
    Umeå universitet, Samhällsvetenskapliga fakulteten, Statsvetenskapliga institutionen.
    Mot en beredskap för kriser och krig?: svenska kommuners prioriteringar och handlingsutrymme under hot i förändring2024Doktorsavhandling, monografi (Övrigt vetenskapligt)
    Abstract [en]

    In recent years, the security structure in Europe has taken a turn for the worse and the threat of inter-state war has moved up on the political agenda. Sweden, for long a neutral and ostensibly peaceful nation, is no exception in this international political trajectory. As a response to changing threat images, both in the face of grey-zone activities and Russian hostility toward Ukraine, the government declared in 2015 that Sweden’s total defence should be (re)built after decades of substantial downscaling. In this process of renewal of the total defence concept, Swedish municipalities find themselves not only as key actors in the crisis preparedness system, but now also as designated novel security actors. Sweden’s 290 municipalities represent a plethora of differences in terms of geography, economy, infrastructure, social and political structures while being responsible for the same essential welfare functions. How do municipalities view the changing national preparedness demands? How are preparedness measures prioritized in relation to everyday welfare needs?

    The aim of this thesis is to understand and explain Swedish municipalities’ perceptions and priorities in the intersection between peacetime crisis preparedness and civil defence, through a socio-technical systems’ perspective. To that end, an ideational analysis has been conducted on policy documents and interviews with municipal representatives, supplemented by a questionnaire. The study shows that the unclear national guidance and instructions given to municipalities create prioritization challenges at the local level. While no indications of preparedness measures being prioritized at the expense of core municipal welfare tasks have been found in this study, the ever-increasing governmental demands may change this order of priority. The dissertation further shows that local level representatives perceive of a general lack of understanding about municipal realities and conditions from the national government, administrative authorities and county council boards. Despite internal and external obstacles however, Swedish municipalities do accept the system changes, and continuously work toward strengthening their civil preparedness based on local capacities and resources.

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  • Disputation: 2024-04-29 13:00 Hörsal UB.A.240 - Lindellhallen 4
    Rahmanian, Ali
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för datavetenskap.
    Edge orchestration for latency-sensitive applications2024Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
    Abstract [en]

    The emerging edge computing infrastructure provides distributed and heterogeneous resources closer to where data is generated and where end-users are located, thereby significantly reducing latency. With the recent advances in telecommunication systems, software architecture, and machine learning, there is a noticeable increase in applications that require processing times within tight latency constraints, i.e. latency-sensitive applications. For instance, numerous video analytics applications, such as traffic control systems, necessitate real-time processing capabilities. Orchestrating such applications at the edge offers numerous advantages, including lower latency, optimized bandwidth utilization, and enhanced scalability. However, despite its potential, effectively managing such latency-sensitive applications at the edge poses several challenges such as constrained compute resources, which holds back the full promise of edge computing.

    This thesis proposes approaches to efficiently deploy latency-sensitive applications on the edge infrastructure. It partly addresses general applications with microservice architectures and party addresses the increasingly more important video analytics applications for the edge. To do so, this thesis proposes various application- and system-level solutions aiming to efficiently utilize constrained compute capacity on the edge while meeting prescribed latency constraints. These solutions primarily focus on effective resource management approaches and optimizing incoming workload inputs, considering the constrained compute capacity of edge resources. Additionally, the thesis explores the synergy effects of employing both application- and system-level resource optimization approaches together.

    The results demonstrate  the effectiveness of the proposed solutions in enhancing the utilization of edge resources for latency-sensitive applications while adhering to application constraints. The proposed resource management solutions, alongside application-level optimization techniques, significantly improve resource efficiency while satisfying application requirements. Our results show that our solutions for microservice architectures significantly improve end-to-end latency by up to 800% while minimizing edge resource usage. Additionally, the results indicate that our application- and system-level optimizations for orchestrating edge resources for video analytics applications can increase the overall throughput by up to 60%. 

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  • Disputation: 2024-05-03 09:00 Major Groove, Umeå
    Groza, Paula Petronela
    Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten). Umeå universitet, Medicinska fakulteten, Wallenberg centrum för molekylär medicin vid Umeå universitet (WCMM).
    RNA-mediated gene expression regulation2024Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
    Abstract [en]

    The regulation of gene expression is a key mechanism that underlies all biological processes, from embryonic development to the onset and progression of various diseases, including cancer. A growing body of evidence places RNA molecules at the center of critical regulatory steps in gene expression. They serve not only as intermediate molecules between DNA and proteins but also act as regulators of processes such as alternative splicing (AS) and translation, among others. This thesis focuses on the role of RNA in gene expression regulation. Specifically, it addresses how intrinsic properties of RNA, RNA chemical modifications, and RNA binding proteins (RBPs) can control gene expression regulatory processes.

    The first part tackles specific aspects of AS in neurodifferentiation. Paper I shows how RBPs affect AS in mouse embryonic stem cells (ESCs). Within this work, we identified ZFP207, a known transcription factor (TF), as an RBP with a crucial role in modulating the AS of key transcripts for neurodifferentiation. Depletion of ZFP207 in mouse ESCs led to abnormal AS patterns and a differentiated cell phenotype.

    The second part (Papers II-IV) focuses on the role of RNA modifications in disease. In Paper II, the publicly available literature linking deregulations of RNA modifications and their regulatory proteins with different diseases was curated. The obtained information was integrated into the 2021 update of the MODOMICS database, the most extensive RNA modifications database to date. Papers III and IV exemplify how two different RNA marks contribute to breast cancer. Paper III shows how METTL3, the enzyme responsible for N6-methyladenosine (m6A) deposition on messenger RNA (mRNA), affects tumorigenesis by modulating AS. METTL3-mediated AS regulation can be done either by depositing m6A at the intron-exon junctions of specific transcripts or on transcripts encoding for splicing and transcription factors, such as MYC. Changes in RNA modifications of ribosomal RNA (rRNA) affect stability, folding, and interactions with other molecules, leading to perturbed translation efficiency (TE). In Paper IV, we focused on the role of 2'-O-methylation, the most abundant rRNA modification, and its catalytic enzyme, fibrillarin (FBL), in triple-negative breast cancer (TNBC). We discovered that certain proto-oncogenes associated with breast cancer displayed a reduction in TE upon FBL depletion. Additionally, we identified 7 2'-O-methylation sites that might mediate TE regulation in a TNBC cellular model. Moreover, our study uncovered alterations in the ribosomal protein composition within the ribosomes of FBL-depleted cells. Our results support the pivotal role of 2'-O-methylation in controlling the translational capabilities of ribosomes in TNBC cells.

    Overall, this work encompasses multiple aspects of gene expression regulation and describes how RNA modifications and RBPs modulate the fate of specific transcripts by controlling AS or translation.

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  • Disputation: 2024-05-03 13:00 HUM.D.220, Humanisthuset, Umeå
    Gustafsson, Peter
    Umeå universitet, Samhällsvetenskapliga fakulteten, Handelshögskolan vid Umeå universitet, Företagsekonomi. Företagsforskarskolan.
    Ships, clouds, and waves: understanding ecosystems in traditional industries2024Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
    Abstract [en]

    This dissertation builds on a jointly phenomenological and theoretical approach to investigate how traditional industries face challenges related to ecosystem innovation. Phenomenologically, it investigates how innovation within the shipbuilding industry affects the activities performed by firms that have traditionally filled the role of suppliers to shipyards. Innovations in digitalisation threaten to upend long-standing relationships and, as a result, have a substantial impact on the structure of the industry, which has a long history of intense competition, long industry cycles, stable products and services, and dependence on global trade. Theoretically, this dissertation is positioned in the growing literature on ecosystems, which takes a particular interest in how innovation creates new interdependencies between actors, interdependencies that need to be aligned for value to materialise. Through this literature, we have an understanding of how innovation can enable new forms of value to reach end users, how firms can orchestrate such activities, and how new entrants can draw on innovation to threaten established industries. However, we have yet to fully consider how ecosystems emerge and are orchestrated in industries characterised by preexisting interdependencies and latent ecosystem structures and the role of complementors in this process.

    These issues are examined through four research papers that build on each other to investigate different aspects of the emergence and orchestration of ecosystems in traditional industries. This research follows an abductive approach, meaning that through iteration between data and theory, new results have been generated. The data for the studies are drawn from two case studies within the shipbuilding industry. The papers present four main findings: first, the emergence of ecosystems is significantly impacted by preexisting interdependencies, particularly incentives to innovate and regulatory dependence. Second, these preexisting interdependencies lead to complementors taking a leading role in innovation that spur the emergence of new ecosystems. Third, this is carried out through market and nonmarket strategies as firms must engage with each other and international organisations. Fourth, the preexisting interdependencies also lead to collective orchestration which requires significant internal coordination to successfully perform but allows for market actors to have greater influence in regulatory matters. I arrive at these results by drawing on insights from resource dependence theory, collective action theory, and corporate political activities. 

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  • Disputation: 2024-05-03 13:15 Hörsal UB.A.2010 - Lindelhallen 1, Umeå
    Henriksson, Andreas
    Umeå universitet, Samhällsvetenskapliga fakulteten, Statsvetenskapliga institutionen.
    A matter of faith?: combatting human trafficking in Thailand & Cambodia2024Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
    Abstract [sv]

    Människohandel är ett globalt fenomen som uppskattas drabba över 49 miljoner människor. I Thailand och Kambodja är människohandel ett utbrett problem, och därför finns det en stor mängd aktörer i dessa länder som arbetar mot människohandel. En vanlig typ av aktör är de religiösa hjälporganisationerna (engelskans faith-based organizations). En enkel definition av religiösa hjälporganisationer är att de har en uttalad religiös identitet och använder sig av religion som en resurs i arbetet. Inom forskningen återstår mycket att utforska när det gäller religiösa hjälporganisationers arbete mot människohandel: till exempel vad som kännetecknar deras arbete mot människohandel, samt hur deras religiösa världsbild formar deras praktiker. Dessutom behövs det mer kunskap om hur religiösa hjälporganisationers explicita religiösa identitet uppfattas av mottagande lokalsamhällen med en annan religiös identitet.

    I den här avhandlingen ställer jag tre forskningsfrågor: (1) Vad gör de religiösa hjälporganisationerna för att motverka människohandel och vad kännetecknar deras praktiker och strategier? (2) Vad är det som påverkar de religiösa hjälporganisationernas strategier? (3) Hur uppfattas de religiösa hjälporganisationernas arbete av de lokala mottagarna i Kambodja och Thailand? Genom att svara på dessa frågor bidrar jag till att öka kunskapen om religiösa aktörers arbete mot människohandel specifikt, men även inom bistånds- och utvecklingsinsatser.

    För att svara på forskningsfrågorna har jag genomfört fallstudier av tre religiösa (kristna) hjälporganisationer som arbetar mot människohandel i Thailand och Kambodja. Inom ramen för dessa fallstudier har jag intervjuat organisationernas personal enskilt, men jag har också intervjuat personal i grupp. Dessutom har jag observerat organisationernas arbete mot människohandel, och granskat dokument som beskriver organisationernas identitet och arbete. I samband med observationerna har jag intervjuat aktörer och personer som finns i de religiösa hjälporganisationernas närhet. Dessa inkluderar sekulära organisationer som arbetar mot människohandel, myndighetsföreträdare samt enskilda individer som berörs av, eller finns i närheten av de religiösa hjälporganisationerna.

    Jag använder mig av ett multidimensionellt teoretiskt ramverk med fyra analytiska dimensioner i syfte att utforska de religiösa hjälporganisationernas arbete mot människohandel. Dessa är (1) särskilda praktiker, (2) idéer, (3) relationer och (4) lokalt mottagande. Det teoretiska ramverket ger mig möjlighet att skapa en djup, omfattande och mångfacetterad förståelse för religiösa hjälporganisationerna som aktörer mot människohandel och som utvecklings- och biståndsaktörer.

    När det gäller min första forskningsfråga, där jag utgår från teoretiska ramverkets särskilda praktiker, visar min analys att religiösa hjälporganisationer som arbetar mot människohandel prioriterar post-traumafasen. Detta innebär t.ex. ett fokus på traumabearbetning samt att (åter)uppbygga självförtroende och moral hos överlevare av människohandel. Ett sådant fokus kan förstås som individualiserade och förandligade lösningar på människohandel, som ofta sker på bekostnad av lösningar som fokuserar på att ändra strukturer. På så sätt deltar de religiösa hjälporganisationerna i terapeutisk styrning (engelskans therapeutic governance), dvs. styrning där fokus förskjuts mot individuellt ansvar med betoning på immateriella värden.

    Min andra forskningsfråga, som utgår från det teoretiska ramverkets andra och tredje dimension om idéer och relationer, handlar om vad som formar organisationernas strategier. Här finner jag att den religiösa världsbilden formar hur de arbetar mot människohandel. Här är de religiösa hjälporganisationernas idéer om holistisk utveckling centralt eftersom det leder till ett fokus på individuell, moralisk och andlig förändring. Även de relationer som religiösa hjälporganisationer har till andra aktörer påverkar. Styrande relationer (engelskans ruling relations) dikterar en begränsad roll för andlighet och religion i arbetet mot människohandel, vilket leder till att de religiösa hjälporganisationerna tonar ner sin religiösa identitet i vissa sammanhang. Det bidrar också till att skapa en tydlig givarprofil för de religiösa hjälporganisationerna som primärt tar emot pengar från enskilda individer, kyrkor och andra religiösa hjälporganisationer, och i mindre utsträckning från institutionella och sekulära givare. Dessa trosbaserade givarnätverk möjliggör för de religiösa hjälporganisationerna att lyfta fram religionens roll för identitet och för arbetet genom att arbeta med religiösa ledare, men även genom att använda tro som en motiverade faktor för förändring. Hur tro och religion används varierar dock beroende på hur central religionen är för en hjälporganisations identitet och arbete (engelskans faith-infusion).

    Den tredje och sista forskningsfrågan, som utgår från det teoretiska ramverkets fjärde dimension om lokalt mottagande, utforskar hur studiens tre kristna hjälporganisationernas arbete mot människohandel tas emot av de lokala buddhistiska samhällena. Min analys visar att de kristna hjälporganisationerna förmår överbrygga religiösa skillnader. Trots de potentiella hindren lyckas de skapa samägarskap (engelskans co-ownership) med de lokala aktörerna och mottagarna när det gäller att formulera vad som orsakar människohandel samt hur människohandel ska bekämpas, och därmed en samsyn kring program och åtgärder. De religiösa hjälporganisationerna har en förmåga att bygga tillit, och förankra och översätta idéer och mål över kulturella och religiösa gränser. Dessutom kan de dra nytta av och bygga på en gemensam religiös världsbild (trots skillnader i religion) i översättningsarbetet mellan de kristna organisationerna och de buddhistiska lokalsamhällena. Sekulära organisationers förståelse för människohandel och hur det ska bekämpas har mindre gemensamt med de buddhistiska lokalsamhällena. Min analys visar också att de religiösa hjälporganisationerna med något nedtonad kristen identitet har lättare att överbrygga avståndet till de sekulära aktörerna. Avhandlingen visar att religiös tro påverkar hur arbetet mot människohandel utformas, genomförs och tas emot. Dock är effekterna och inflytandet av religiös tro på arbetet mot människohandel kontextspecifik, och beror på hur tron interagerar med kulturella normer och värderingar, liksom materiella förhållanden. 

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