| 1. |
- Baudin, Maria, 1982-
(författare)
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Rift Valley fever : consequences of virus-host interactions
- 2016
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Rift Valley fever virus (RVFV) is a mosquito-borne virus which has the ability to infect a large variety of animals including humans in Africa and Arabian Peninsula. The abortion rate among these animals are close to 100%, and young animals develop severe disease which often are lethal.In humans, Rift Valley fever (RVF) presents in most cases as a mild illness with influenza-like symptoms. However, in about 8% of the cases it progresses into a more severe disease with a high case fatality rate. Since there is such a high abortion rate among infected animals, a link between human miscarriage and RVFV has been suggested, but never proven.We could in paper I for the first time show an association between acute RVFV infection and miscarriage in humans. We observed an increase in pregnant women arriving at the Port Sudan Hospital with fever of unknown origin, and several of the patients experienced miscarriage. When we analysed their blood samples for several viral diseases we found that many had an acute RVFV infection and of these, 54% experienced a miscarriage. The odds of having a miscarriage was 7 times higher for RVFV patients compared to the RVFV negative women of which only 12% miscarried. These results indicated that RVFV infection could be a contributing factor to miscarriage.RVFV is an enveloped virus containing the viral glycoproteins n and c (Gn and Gc respectively), where Gn most likely is responsible for the initial cellular contact. The protein DC-SIGN on dendritic cells and the glycosaminoglycan heparan sulfate has been suggested as cellular receptors for RVFV, however other mechanisms are probably also involved in binding and entry. Charge is a driving force for molecular interaction and has been shown to be important for cellular attachment of several viruses, and in paper II we could show that when the charge around the cells was altered, the infection was affected. We also showed that Gn most likely has a positive charge at a physiological pH.When we added negatively charged molecules to the viral particles before infection, we observed a decreased infection efficiency, which we also observed after removal of carbohydrate structures from the cell surface.Our results suggested that the cellular interaction partner for initial attachment is a negatively charged carbohydrate. Further investigations into the mechanisms of RVFV cellular interactions has to be undertaken in order to understand, and ultimately prevent, infection and disease.There is currently no vaccine approved for human use and no specific treatments for RVF, so there is a great need for developing safe effective drugs targeting this virus. We designed a whole-cell based high-throughput screen (HTS) assay which we used to screen libraries of small molecular compounds for anti-RVFV properties. After dose-response and toxicity analysis of the initial hits, we identified six safe and effective inhibitors of RVFV infection that with further testing could become drug candidates for treatment of RVF. This study demonstrated the application of HTS using a whole-cell virus replication reporter gene assay as an effective method to identify novel compounds with potential antiviral activity against RVFV.
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| 2. |
- Tordön, Rikard, Doktorand, 1969-
(författare)
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Health, Experienced Support and School Performance among Children in Out-of-home care
- 2020
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Children in out-of-home care (OHC) have higher risks for developing poorer health and school achievement, being subjected to more abuse experiences, as well as negative long-term outcomes related to occupational performance, socioeconomic status, addiction, and criminality. Research related to OHC children is fragmented and the effects of interventions are under-studied.This thesis aimed to explore health, abuse, support, and preconditions for school among children in OHC and to assess changes after an intervention targeting foster children’s school performance.Paper I compared OHC pupils in last year high school to non-OHC peers in a national survey with 5 839 pupils. The study showed that risks of abuse and poor mental health are evident for adolescents in out-of-home care. Also, results indicated a lower disclosure rate of sexual abuse, particularly to police or social services.Paper II compared OHC pupils to peers in birth parent care by analyzing responses in four consecutive year surveys in a regional sample comprising 23 798 pupils in 8th-year compulsory and 2nd-year high school. Responses from the 311 pupils in OHC showed poorer outcomes than did birth-parent care peers in perceived satisfaction with social life and relations, trust to other persons in different relations, abuse experiences online, and sense of security in the school and at home. These results also applied when compared to a subset of pupils living with a single birth parent.Paper III analyzed prospective test and questionnaire data of intelligence, adaptive behavior, mathematics, literacy skills, and psychosocial wellbeing from 856 children in foster care. Results revealed poorer preconditions for school performance of between 0.5 and 1.0 standard deviations below age-standardized norms. The analysis also provided results regarding different intelligence domains, where working memory showed the lowest scores while perceptual functioning were close to norms. Boys generally scored poorer than girls except in mathematics.Paper IV explored the effects of a school-based intervention, Skolfam, on a subset of Paper III cohort (n= 475). Results showed improved skills in higher-order cognitive executive functions such as reading comprehension, sentence chains, mathematics, and intelligence. For less complex cognitive functions, affective functioning or psychosocial symptoms, no improvements were seen, except for reduced hyperactivity.Conclusion: The studies confirm that children in OHC have poorer mental health, are less satisfied with social life, have more adverse experiences both online and in real life and have poorer preconditions for school performance than do non-OHC peers. Importantly, Skolfam intervention can partially enhance preconditions for school performance. Further studies on longitudinal risk, with a design to identify specific protective factors, development of school-related competencies and ways to support OHC children in school are needed.
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| 3. |
- Bergström, Göran, 1977-
(författare)
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Från svensk malmexport till utländsk etablering : Grängesbergsbolagets internationalisering 1953-1980
- 2009
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The main purpose of this thesis is to analyze the internationalisation of the Grängesberg Company from 1953 to 1980. The strategies that the company used and the knowledge it gained by participating in international mining projects are studied. The first and largest mining activity abroad was the Lamco project in Liberia. By transferring the company’s competence and knowledge of mining activities to Liberia, the Grängesberg Company used an international strategy of horizontal integration. The company’s contacts were of importance to start the production in 1963. The main ambition was thereafter to negotiate new long-term contracts in order to create stability for the project in the 1960s and the 1970s. Through its involvement in the Lamco project, the Grängesberg Company also acquired shares in a Belgian steel company and became half-owner with the Liberian state in a foreign shipping company. The experience and knowledge that the company gained in the Lamco project was used to increase its internationalisation in the 1970s. Appointing a Mineral Project Group, it investigated existing mineral projects abroad and formulated new internationalisation strategies such as vertical integration and diversification. The main motive for the further expansion abroad in the mining area was a need for resources for its domestic production. The most important outcome was the acquisition of a Canadian copper company, and the company integrated backwards to gain access to copper. The Grängesberg Company also used its competence by doing prospecting work in New Caledonia, Peru and Canada and consultant work in mining projects in Iran and Saudi Arabia in the 1970s. The study has shown that further international expansion became limited because of the downturn of the international economy in the 1970s, but also because of the company’s cautious attitude towards the political risks that were associated with international mining projects.
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| 4. |
- Bergström, Göran, 1964, et al.
(författare)
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Prevalence of Subclinical Coronary Artery Atherosclerosis in the General Population
- 2021
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Ingår i: Circulation. - Philadelphia : American Heart Association. - 0009-7322 .- 1524-4539. ; 144:12, s. 916-929
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Tidskriftsartikel (refereegranskat)abstract
- Background: Early detection of coronary atherosclerosis using coronary computed tomography angiography (CCTA), in addition to coronary artery calcification (CAC) scoring, may help inform prevention strategies. We used CCTA to determine the prevalence, severity, and characteristics of coronary atherosclerosis and its association with CAC scores in a general population.Methods: We recruited 30 154 randomly invited individuals age 50 to 64 years to SCAPIS (the Swedish Cardiopulmonary Bioimage Study). The study includes individuals without known coronary heart disease (ie, no previous myocardial infarctions or cardiac procedures) and with high-quality results from CCTA and CAC imaging performed using dedicated dual-source CT scanners. Noncontrast images were scored for CAC. CCTA images were visually read and scored for coronary atherosclerosis per segment (defined as no atherosclerosis, 1% to 49% stenosis, or ≥50% stenosis). External validity of prevalence estimates was evaluated using inverse probability for participation weighting and Swedish register data.Results: In total, 25 182 individuals without known coronary heart disease were included (50.6% women). Any CCTA-detected atherosclerosis was found in 42.1%; any significant stenosis (≥50%) in 5.2%; left main, proximal left anterior descending artery, or 3-vessel disease in 1.9%; and any noncalcified plaques in 8.3% of this population. Onset of atherosclerosis was delayed on average by 10 years in women. Atherosclerosis was more prevalent in older individuals and predominantly found in the proximal left anterior descending artery. Prevalence of CCTA-detected atherosclerosis increased with increasing CAC scores. Among those with a CAC score >400, all had atherosclerosis and 45.7% had significant stenosis. In those with 0 CAC, 5.5% had atherosclerosis and 0.4% had significant stenosis. In participants with 0 CAC and intermediate 10-year risk of atherosclerotic cardiovascular disease according to the pooled cohort equation, 9.2% had CCTA-verified atherosclerosis. Prevalence estimates had excellent external validity and changed marginally when adjusted to the age-matched Swedish background population.Conclusions: Using CCTA in a large, random sample of the general population without established disease, we showed that silent coronary atherosclerosis is common in this population. High CAC scores convey a significant probability of substantial stenosis, and 0 CAC does not exclude atherosclerosis, particularly in those at higher baseline risk.
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| 5. |
- Bergström, Ulf, 1974-
(författare)
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Temporality and the Semantics of the Biblical Hebrew Verbal System
- 2014
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- This dissertation investigates the semantic factors behind the temporal meanings of the Biblical Hebrew (BH) verbal forms. Four different forms are studied, viz. qotel, yiqtol-L, qatal, and yiqtol-S. On the basis of comparative and historical linguistic studies, qotel and yiqtol-L are classified as originally progressive forms, whereas qatal and yiqtol-S are classified as originally resultative ones. Since there is a tendency in BH to use the progressive subgroup for future meaning and the resultative subgroup for past meaning, a key to understanding how temporality is expressed in this language is to understand the meaning of the progressive and the resultative verbal types.In critical dialogue with modern typological linguistic research, a unified theory of aspect and tense is developed. The theory defines the meanings of the progressive and resultative verbal types in terms of a distinct kind of aspect, called “stage-based aspect”, and describes how tense meanings arise through reanalysis of these aspectual meanings, a process called temporalization. It is argued that progressive aspect is a basic meaning in qotel and yiqtol-L, and that resultative aspect is basic in qatal and yiqtol-S in its so-called “consecutive” form, wayyiqtol. The study investigates various verbal usages, showing where the stage-aspectual meanings are invariant and where they have been overturned as a consequence of temporalization.Another major question concerns the semantic difference between the forms with shared aspectual meanings. On the basis of the semiotic theories of Bühler and others, it is suggested that yiqtol-L and yiqtol-S (here: yiqtol) are distinguished from qotel and qatal with regard to their appeal function. Full appeal function characterizes utterances that prompt the listener to immediate action. Verbal forms available for this function in BH are qatal and qotel, as well as the imperative. By contrast, the appeal to action in utterances employing yiqtol is invariably non-existent, or mitigated. Hence, reduced appeal function is a semantic feature of yiqtol. This feature may explain why temporalized meanings are especially favoured by yiqtol, since non-present meaning is one among several factors that reduce the appeal function of an utterance.
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| 6. |
- Marttila, Marko, 1972-
(författare)
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Cellular receptors for species B adenoviruses
- 2007
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Adenoviruses belong to the most common human pathogens. The severity of infection varies greatly, from subclinical to lethal, depending on the virus type and immune status of the infected host. The 51 known human adenovirus serotypes are divided into six species (A-F) based on characteristics such as tropism. Species B adenoviruses, which are the subjects of this thesis, are further divided into subspecies B:1 that contains Ad3, Ad7, Ad16, Ad21 and Ad50 and subspecies B:2 that contains Ad11, Ad14, Ad34 and Ad35. Species B adenoviruses primarily cause ocular and respiratory tract infections, but certain serotypes (Ad11, Ad34 and Ad35) are also associated with renal disease. The main aim of this thesis was to identify and characterize cellular receptors for species B adenoviruses. This will ultimately help to understand the diverse tropism shown by different adenoviruses and perhaps contribute to development of antivirals. Also, since adenoviruses are among the most commonly used vector for gene therapy it is of importance to characterize the initial steps of adenovirus life cycle. Members of species B adenoviruses have been shown to utilize both the complement regulating membrane cofactor protein (MCP), i.e. CD46, and a still unknown receptor. CD80 and CD86, usually found on antigen-presenting cells, have also been suggested as receptors We found first that Ad11 used CD46 as a cellular receptor on respiratory A549 cells, and subsequently that CD46 is a cellular receptor for all species B adenovirus serotypes, except for adenovirus types 3 and 7, using cells that represent the tropism of species B adenoviruses, i.e. respiratory, conjunctival and renal epithelial cells. We further compared the relative roles of CD46 with CD80 and CD86 using cells that represent species B adenovirus tropism. Using soluble candidate receptors and antibodies against corresponding receptors to challenge virus binding to and infection of cells, we found that on these cells, CD46 is a cellular receptor for all species B adenoviruses except Ad3 and Ad7, and that CD80 and CD86 do not play an important role. We have further pinpointed the interaction site for Ad11 on CD46 by X-ray crystallography. The extracellular region of CD46 contains four short consensus repeats (SCR1-4) of which the outermost N-terminal SCR1 and SCR2 mediate binding to Ad11. This interaction was confirmed by inhibiting infection and binding of Ad11 to A549 cells using soluble SCR1-2 fragments. Surprisingly the conformation of bound CD46 differs profoundly from its unbound state, with the bent surface structure straightened into an elongated rod. Viral proteins can sometimes undergo large conformational changes upon receptor binding, but this is, to the best of our knowledge, the first example of a virus protein dramatically changing the overall structure of its receptor. CD46 serves as a receptor for a large number of viral and bacterial pathogens and it is structurally and functionally related to other viral receptors such as CD21 and CD55. The mode of interaction presented here may serve as a conceptual framework for studies of many other receptors that are constructed from SCR domains.
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| 7. |
- Strömvall, Kerstin, 1980-
(författare)
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Extratumoral effects of highly aggressive prostate cancer
- 2017
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Prostate cancer (PC) is the most common cancer in Sweden. Most patients have slow growing tumors that will not cause them any harm within their lifetime, but some have aggressive tumors and will die from their disease. The ability of current clinical practice to predict tumor behavior and disease outcome is limited leading to both over- and undertreatment of PC patients. The men who die from their disease are those that develop metastases. It is therefore of great value to find better and more sensitive prognostic techniques, so that metastatic spread can be detected (or predicted) at an early time point, and so that appropriate treatment can be offered to each subgroup of patients. The aim of this thesis was to investigate if, and by what means, highly aggressive prostate tumors influence extratumoral tissues such as the non-malignant parts of the prostate and regional lymph nodes (LN), and also if any of our findings could be of prognostic importance. Gene- and protein expression analysis were the main methods used to address these questions. Our research group has previously introduced the expression Tumor Instructed (Indicating) Normal Tissue (TINT), and we use the term TINT-changes when referring to alterations in non-malignant tissue due to the growth of a tumor nearby or elsewhere in the body. In the Dunning rat PC-model we found that MatLyLu (MLL)-tumors, having a high metastatic ability, caused pre-metastatic TINT-changes that differ from those caused by AT1-tumors who have low metastatic ability. Prostate-TINT surrounding MLL-tumors had elevated immune cell infiltration, and gene ontology enrichment analysis suggested that biological functions promoting tumor growth and metastasis were activated in MLL- while inhibited in AT1-prostate-TINT. In the regional LNs we found signs of impaired antigen presentation, and decreased quantity of T cells in the MLL-model. One of the downregulated genes in the MLL-LNs was Siglec1 (also known as Cd169), expressed by LN resident macrophages that are important for antigen presentation. When examining metastasis-free LN tissue from PC patients we found CD169 expression to be a prognostic factor for PC-specific survival, and reduced expression was linked to an increased risk of PC-specific death. Some of our findings in prostate- and LN-TINT could be seen already when the tumors were very small suggesting that differences in TINT-changes between tumors with different metastatic capability can be detected early in tumor progression. However, before coming of use in the clinic more research is needed to better define a suitable panel of prognostic TINT-factors as well as the right time window of when to use them.
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| 8. |
- Tornhill, Sofie, 1974-
(författare)
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Capital Visions : The Politics of Transnational Production in Nicaragua
- 2010
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- In processes of economic integration, neoliberal discourse and corresponding notions of development comprise some of the most readily available imaginaries of political and social interaction and change. However, these processes are always also locally produced and negotiated. Engaging with discourse theory, Marxism and postcolonial feminist theory, this dissertation brings together “macro” and “micro” aspects of globalization. The aim is to interrogate discursive reinforcements of and challenges to global orders of production and divisions of labor. With a focus on representations of Free Trade Zones (FTZs), which are tax-exempted enclaves for export production, the study explores competing meanings attributed to the operation of transnational capital in Nicaragua. Based on policy documents, political speeches, promotional videotapes and interviews, the political rhetoric of two governments with competing agendas is analyzed: the neoliberal/conservative government of the Liberal Constitutionalist Party (2002–2007), which framed the FTZs in terms of national progress, and the leftist government of the Sandinista National Liberation Front (2007– ), which attempts to reconnect to the country’s revolutionary past. In this way efforts to formulate legitimate political agendas in the context of shifting relations between states and markets are detailed, together with constructions of citizens and workers along differentiations of class and gender. Relying on interviews with FTZ workers, the study examines ways to interpret, inhabit or resist imperative subject positions at the intersections of contending projects of nation-building and transnational orders of production, in conjunction with a discussion of the uneasy distinction between representation and appropriation that troubles transnational feminist research projects.
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| 9. |
- Abdellah, Tebani, et al.
(författare)
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Integration of molecular profiles in a longitudinal wellness profiling cohort.
- 2020
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Ingår i: Nature communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 11:1
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Tidskriftsartikel (refereegranskat)abstract
- An important aspect of precision medicine is to probe the stability in molecular profiles among healthy individuals over time. Here, we sample a longitudinal wellness cohort with 100 healthy individuals and analyze blood molecular profiles including proteomics, transcriptomics, lipidomics, metabolomics, autoantibodies andimmune cell profiling, complementedwith gut microbiota composition and routine clinical chemistry. Overall, our results show high variation between individuals across different molecular readouts, while the intra-individual baseline variation is low. The analyses show that each individual has a unique and stable plasma protein profile throughout the study period and that many individuals also show distinct profiles with regards to the other omics datasets, with strong underlying connections between the blood proteome and the clinical chemistry parameters. In conclusion, the results support an individual-based definition of health and show that comprehensive omics profiling in a longitudinal manner is a path forward for precision medicine.
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| 10. |
- Baldanzi, Gabriel, et al.
(författare)
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OSA Is Associated With the Human Gut Microbiota Composition and Functional Potential in the Population-Based Swedish CardioPulmonary bioImage Study
- 2023
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Ingår i: Chest. - : Elsevier. - 0012-3692 .- 1931-3543. ; 164:2, s. 503-516
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Obstructive sleep apnea (OSA) is a common sleep-breathing disorder linked to increased risk of cardiovascular disease. Intermittent hypoxia and intermittent airway obstruction, hallmarks of OSA, have been shown in animal models to induce substantial changes to the gut microbiota composition and subsequent transplantation of fecal matter to other animals induced changes in blood pressure and glucose metabolism.RESEARCH QUESTION: Does obstructive sleep apnea in adults associate with the composition and metabolic potential of the human gut microbiota?STUDY DESIGN AND METHODS: We used respiratory polygraphy data from up to 3,570 individuals aged 50-64 from the population-based Swedish CardioPulmonary bioImage Study combined with deep shotgun metagenomics of fecal samples to identify cross-sectional associations between three OSA parameters covering apneas and hypopneas, cumulative sleep time in hypoxia and number of oxygen desaturation events with gut microbiota composition. Data collection about potential confounders was based on questionnaires, on-site anthropometric measurements, plasma metabolomics, and linkage with the Swedish Prescribed Drug Register.RESULTS: We found that all three OSA parameters were associated with lower diversity of species in the gut. Further, the OSA-related hypoxia parameters were in multivariable-adjusted analysis associated with the relative abundance of 128 gut bacterial species, including higher abundance of Blautia obeum and Collinsela aerofaciens. The latter species was also independently associated with increased systolic blood pressure. Further, the cumulative time in hypoxia during sleep was associated with the abundance of genes involved in nine gut microbiota metabolic pathways, including propionate production from lactate. Lastly, we observed two heterogeneous sets of plasma metabolites with opposite association with species positively and negatively associated with hypoxia parameters, respectively.INTERPRETATION: OSA-related hypoxia, but not the number of apneas/hypopneas, is associated with specific gut microbiota species and functions. Our findings lay the foundation for future research on the gut microbiota-mediated health effects of OSA.
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