| 1. |
- Ahlstedt, Sara, 1977-
(författare)
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The Feeling of Migration : Narratives of Queer Intimacies and Partner Migration
- 2016
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- This dissertation analyzes narratives of queer partner migration, that is, a family-tie migration in which one of the partners of a relationship has migrated in order for the partners to be together, and where the partners queer the migration in the sense that they have a non-normative sexuality and/or gender identity. The purpose of the study is to examine how queer partner migrants and their Swedish partners experience the migration process – which continues also once the administrative process has been completed – by analyzing the emotions and feelings that emerge in the process. The study is a contribution to research on privileged migration as well as intimate migration.The focus is the queer partner migration relationship, and what emotions and feelings ‘do’ to this relationship, but also how emotions and feelings structure the migration process. The study analyzes the work three different emotions – love, loss, and belonging – do in these migration processes, and how this work is described in the participant narratives. Migrant participants have migrated from different parts of the world (Africa, Europe, Latin America, and North America), making it possible to analyze what emotions and feelings do in this particular migration process from the point of view of nationality and, in particular, proximity to ‘Western-ness,’ race, and language as well as how privileges connected to these positions come to matter in the process.The dissertation is an ethnographic interview study in which both migrants and Swedish partners have been interviewed. The interview material consists of a combination of couple interviews and individual interviews.By using affect theories and the concept of queer phenomenology, the dissertation shows how the work that emotions and feelings do in migration processes is connected to gender identity, sexual identity, race and whiteness, nationality, perceived proximity to Western-ness, class, language, and the migration narrative the migrating partner is (or is not) written into by way of the country they have migrated from. This is analyzed in relation to the theoretical frameworks of entanglement, homonationalism, and intimate citizenship.The analysis shows that emotions and feelings structure the migration process for both more privileged and less privileged migrants, but in different ways. The understanding of who ‘is’ a migrant, and the preparedness for the feelings that arise in a migration process, are tied to the positions mentioned above and the privileges these positions give, or do not give, the migrant access to. By focusing on emotions and feelings and what these do, the study also illustrates how the migration process affects the non-migrating partner as this partner engages in emotional labour to ‘make’ the migrating partner ‘Swedish.’ Through their the migrating partner, the non-migrating partner is also aligned in a way that makes them a little bit less ‘Swedish,’ contributing to the non-migrating partner being ‘stopped’ in ways they have usually not experienced before. The study further shows how migration processes produces inequality, and the difficulties that arise when the couples try to live up to the Swedish ideal of the equal relationship.The interviews are analyzed as narratives, and both narratives and storytelling are important throughout the dissertation, not only as the method used in the analysis but as the form of the dissertation, making it a kind of super structure organizing the writing. Writing (how to write accessibly and interesting) and reading (how to write in order to invite an open and active reading) are important aspects of the dissertation.
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| 2. |
- Aidoukovitch, Alexandra, et al.
(författare)
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The host defense peptide LL-37 is internalized by human periodontal ligament cells and prevents LPS-induced MCP-1 production
- 2019
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Ingår i: Journal of Periodontal Research. - : Wiley. - 0022-3484 .- 1600-0765. ; 54:6, s. 662-670
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Tidskriftsartikel (refereegranskat)abstract
- Objective: The human host defense peptide LL-37 both shows antimicrobial effects and modulates host cell properties. Here, we assess the effects of synthesized LL-37 on lipopolysaccharide (LPS)-induced inflammation in human periodontal ligament (PDL) cells and investigates underlying mechanisms. Background: LL-37 has been detected in the periodontal tissues, but its functional importance for PDL cell innate immune responses is not known. Methods: Human PDL cells were obtained from premolars extracted on orthodontic indications. Cellular pro-inflammatory monocyte chemoattractant protein-1 (MCP-1) mRNA expression was determined using quantitative real-time RT-PCR. MCP-1 protein production was assessed by western blot and ELISA. Internalization of LL-37 by PDL cells was visualized by immunocytochemistry. Nuclear factor kappa-light-chain-enhancer of activated B-cell (NF-κB) activity was assessed by western blot of phosphorylated p65, phosphorylated p105, and IκBα proteins. Binding of LL-37 to PDL cell DNA was determined by isolation and purification of DNA and dot blot for LL-37 immunoreactivity. Results: Treatment with LL-37 (1 µmol/L) for 24 hours prevented LPS-induced stimulation of MCP-1 expression analyzed both on transcript and on protein levels. Stimulation with LL-37 (1 µmol/L) for 24 hours had no effect on toll-like receptor (TLR)2 and TLR4 transcript expression, suggesting that LL-37 acts downstream of the TLRs. Preincubation with LL-37 for 60 minutes followed by stimulation with LPS for 24 hours in the absence of LL-37 completely prevented LPS-evoked MCP-1 transcript expression, implying that LL-37 acts intracellularly and not via binding and neutralization of LPS. In PDL cells stimulated with LL-37 for 60 minutes, the peptide was internalized as demonstrated by immunocytochemistry, suggesting an intracellular mechanism of action. LL-37 immunoreactivity was observed both in the cytosol and in the nucleus. Downregulation of LPS-induced MCP-1 by LL-37 was not mediated by reduction in NF-κB activity as shown by unaltered expression of phosphorylated p65, phosphorylated p105, and IκBα NF-κB proteins in the presence of LL-37. Immunoreactivity for LL-37 was observed in PDL cell DNA treated with but not without 0.1 and 1 µmol/L LL-37 for 60 minutes in vitro. Conclusion: LL-37 abolishes LPS-induced MCP-1 production in human PDL cells through an intracellular, NF-κB-independent mechanism which probably involves direct interaction between LL-37 and DNA.
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| 3. |
- Anders, Emma, et al.
(författare)
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LL-37-induced human osteoblast cytotoxicity and permeability occurs independently of cellular LL-37 uptake through clathrin-mediated endocytosis
- 2018
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Ingår i: Biochemical and Biophysical Research Communications. - : Elsevier BV. - 0006-291X. ; 501:1, s. 280-285
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Tidskriftsartikel (refereegranskat)abstract
- The host defense peptide LL-37 is cytotoxic for bacteria but it has also been reported to reduce host cell viability through an intracellular mechanism. LL-37-evoked cytotoxicity may be involved in the loss of bone tissue in periodontitis which is an inflammatory disease characterized by high concentrations of LL-37 observed locally in the periodontal tissue at the inflammation process. Here, we showed that LL-37 reduced human osteoblast-like MG63 cell viability assessed by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and increased plasma membrane permeability determined by measuring intracellular Ca2+ levels and lactate dehydrogenase (LDH) release. Treatment with chlorpromazine, a well-recognized inhibitor of clathrin-mediated endocytosis, reduced cellular uptake of synthesized LL-37 b y about 30% assessed by Western blotting and ELISA, while filipin, an inhibitor of caveolin-mediated endocytosis, had no effect. The chlorpromazine-induced attenuation of LL-37 uptake was not associated with modulation of LL-37-induced cytotoxicity and LL-37-evoked plasma membrane permeability. Clathrin heavy chain 2 is a major protein of the polyhedral coat of coated pits and vesicles encoded by clathrin heavy chain like 1 gene. Down-regulation of clathrin heavy chain like 1 gene activity by siRNA reduced uptake of LL-37 but did not affect LL-37-induced cytotoxicity and permeability. Thus, we show, using both a pharmacological approach and knockdown of clathrin heavy chain like 1 expression, that LL-37-induced MG63 cell cytotoxicity and permeability occurs independently of LL-37 uptake via clathrin-mediated endocytosis.
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| 4. |
- Dahl, Sara
(författare)
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Optic nerve hypoplasia in children : prevalence, associated disorders and genetic causes
- 2018
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Optic nerve hypoplasia (ONH) is a congenital ocular malformation with a thin optic nerve in one or both eyes. ONH has been associated with neurodevelopmental disorders and pituitary dysfunction, but the prevalence of these comorbidities are still unknown, especially in children with less severe visual impairment and unilateral disease. The aims of this thesis were to examine the prevalence of ONH in children, to determine the prevalence of intellectual disability, autism spectrum disorder, motor impairment, and pituitary dysfunction in unilateral and bilateral disease, as well as to identify genetic variants underlying ONH. Methods: In study I, a population-based cohort of patients with ONH was established including patients who were diagnosed with ONH, below 20 years of age, and living in Stockholm in December 2009. Ophthalmological assessments were performed, and the Five to Fifteen parent questionnaire (FTF) was used to screen for developmental problems. Subsequently, study II and study III were population-based cross-sectional cohort studies. In study II, neurodevelopmental disorders were confirmed by the FTF, neurological assessments, reviewing previous neuropsychological investigations, or conducting neuropsychological tests. In study III, motor impairments were assessed using a specific protocol and previous neuroradiology was reviewed. Blood sampling was performed to screen for pituitary dysfunction together with analysis of growth curves and medical history. Study IV included 29 patients with ONH who were analysed with array comparative genomic hybridization followed by whole genome sequencing and in silico filtering of single nucleotide variants in 42 candidate genes. Rare variants were verified by Sanger sequencing. Results: The prevalence of ONH in children in Stockholm was 17.3/100 000. Unilateral ONH was almost as common as bilateral (45%). Intellectual disability was more common in bilateral ONH than in unilateral ONH (56% vs 9%, p< 0.001). Autism spectrum disorders were diagnosed in 17%, without correlation to laterality. Motor impairments were identified in 47% of the patients and were significantly more prevalent in bilateral ONH. In contrast, pituitary hormone deficiency (PHD) was confirmed in 29% of the cohort and 19% had multiple PHD, without correlation to laterality. Furthermore, presence of structural pituitary abnormalities had a very high sensitivity for PHD. Finally, we identified three rare variants in COL4A1 and three rare variants in COL4A2, of which two were assessed as likely pathogenic. In addition, we found an interesting rare variant in OPA1 and two other likely pathogenic variants in SOX5 and PAX6. Conclusions: ONH is a common ocular malformation in children, with a prevalence of 17.3/100 000 in Stockholm. Unilateral ONH seems to be as common as bilateral. Children with both unilateral and bilateral ONH have a high risk of neurodevelopmental disorders and PHD, but bilateral ONH increases the risk of intellectual disability, motor impairment, and brain abnormalities. These findings need to be considered when designing screening, care, and follow-up programs. Our genetic study suggests that a genetic cause of ONH is more common than previously reported and highlights COL4A1 and COL4A2 as candidate genes.
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| 5. |
- Dahl, Sara, et al.
(författare)
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The host defense peptide LL-37 triggers release of nucleic acids from human mast cells
- 2018
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Ingår i: Peptides. - : Elsevier BV. - 0196-9781 .- 1873-5169. ; 109, s. 39-45
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Tidskriftsartikel (refereegranskat)abstract
- The human host defense peptide LL-37 possesses antimicrobial activity but also affects host cell function and viability. Mast cells are involved in innate immunity but no data have been presented on effects of LL-37 on human mast cell viability and export of nucleic acids. Here, we demonstrated by immunofluorescence microscopy that synthesized LL-37 was internalized by human LAD2 mast cells and detected both in cytoplasm and nucleus. Treatment with high (4 and 10 μM) but not low (1 μM) concentrations of LL-37 for 4 h reduced cell viability assessed by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Stimulation with 10 μM LL-37 for 4 h enhanced export of nucleic acids, total protein and lactate dehydrogenase (LDH), suggesting that both nuclear and plasma membranes are permeabilized by LL-37. Although LL-37 triggered release of nucleic acids, no extracellular trap-like structures were observed by laser scanning confocal microscopy of cells incubated with the plasma membrane impermeable nucleic acid fluorophore SYTOX-Green, indicating that LL-37 promotes export of nucleic acids but not formation of extracellular traps. On the other hand, phorbol-12-myristate-13-acetate (PMA), which is a well-known inducer of extracellular traps, stimulated export of nucleic acids and also formation of extracellular trap-like structures. However, PMA had no effect on export of either total protein or LDH. Hence, LL-37 and PMA seem to stimulate export of nucleic acids from LAD2 mast cells through different pathways. In conclusion, we demonstrate that LL-37 triggers release of nucleic acids from human mast cells but not the formation of extracellular trap-like structures.
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| 6. |
- Eskelund, Christian W., et al.
(författare)
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TP53 mutations identify younger mantle cell lymphoma patients who do not benefit from intensive chemoimmunotherapy
- 2017
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Ingår i: Blood. - : American Society of Hematology. - 0006-4971 .- 1528-0020. ; 130:17, s. 1903-1910
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Tidskriftsartikel (refereegranskat)abstract
- Despite recent advances in lymphoma treatment, mantle cell lymphoma (MCL) remains incurable, and we are still unable to identify patients who will not benefit from the current standard of care. Here, we explore the prognostic value of recurrent genetic aberrations in diagnostic bone marrow (BM) specimens from 183 younger patients with MCL from the Nordic MCL2 and MCL3 trials, which represent current standard-of-care regimens. In the univariate model, mutations of TP53 (11%) and NOTCH1 (4%), and deletions of TP53 (16%) andCDKN2A(20%),weresignificantly associatedwithinferioroutcomes(togetherwithMIPI, MIPI-c, blastoidmorphology, and Ki67 > 30%); however, inmultivariate analyses, only TP53 mutations (HR, 6.2; P <.0001) retained prognostic impact for overall survival (OS), whereas TP53 mutations (HR, 6.9; P <.0001) andMIPI-c high-risk (HR, 2.6; P5.003) had independent prognostic impact on time to relapse. TP53-mutated cases had a dismal outcome, with a median OS of 1.8 years, and 50% relapsed at 1.0 years, compared to a median OS of 12.7 years for TP53-unmutated cases (P <.0001). TP53 mutations were significantly associated with Ki67 > 30%, blastoid morphology, MIPI high-risk, and inferior responses to both induction- and high-dose chemotherapy. In conclusion, we show that TP53mutations identify a phenotypically distinct and highly aggressive form of MCL with poor or no response to regimens including cytarabine, rituximab, and autologous stem-cell transplant (ASCT). We suggest patients with MCL should be stratified according to TP53 status, and that patients with TP53 mutations should be considered for experimental frontline trials exploring novel agents.
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| 7. |
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| 8. |
- Kee, Nigel, et al.
(författare)
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Single-Cell Analysis Reveals a Close Relationship between Differentiating Dopamine and Subthalamic Nucleus Neuronal Lineages
- 2017
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Ingår i: Cell Stem Cell. - : Elsevier BV. - 1934-5909 .- 1875-9777. ; 20:1, s. 29-40
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Tidskriftsartikel (refereegranskat)abstract
- Stem cell engineering and grafting of mesencephalic dopamine (mesDA) neurons is a promising strategy for brain repair in Parkinson's disease (PD). Refinement of differentiation protocols to optimize this approach will require deeper understanding of mesDA neuron development. Here, we studied this process using transcriptome-wide single-cell RNA sequencing of mouse neural progenitors expressing the mesDA neuron determinant Lmx1a. This approach resolved the differentiation of mesDA and neighboring neuronal lineages and revealed a remarkably close relationship between developing mesDA and subthalamic nucleus (STN) neurons, while also highlighting a distinct transcription factor set that can distinguish between them. While previous hESC mesDA differentiation protocols have relied on markers that are shared between the two lineages, we found that application of these highlighted markers can help to refine current stem cell engineering protocols, increasing the proportion of appropriately patterned mesDA progenitors. Our results, therefore, have important implications for cell replacement therapy in PD.
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| 9. |
- Kjellsson, Sara, 1975-
(författare)
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Sick of Work? : Questions of Class, Gender and Self-Rated Health
- 2017
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- This thesis examines two aspects of social inequalities in health with three empirical studies that are based on the Swedish Level of Living survey (LNU): The relationship between accumulated occupational class positions during adulthood and health and the class-specific nature of gender differences in health. Previous research continuously finds that there are health differences by class and gender, but less is known about the extent to which accumulated class experiences in adulthood are related to health or how gender differences vary by class. The overall conclusion in this thesis is that occupational class experiences matters for health, both as historical and current experiences. Furthermore, the results highlight the importance of taking class into consideration when examining health differences between men and women, as the mechanisms that underlie the gender gaps in health are not necessarily the same for all classes. The studies can be outlined as:Study I: Class differences in working conditions is a mechanism that underlies class inequalities in health. The working class is generally more exposed to adverse working environments than non-manual employees, and when the wear and tear of these conditions accumulate over time, the length of this exposure may contribute to class inequalities in health. Thereby, accumulated time in the working class is studied as a partial explanation for class differences in health. The results suggest that the duration of time in the working class is related to a higher probability of less than good self-rated general health (SRH), given current class position. This association was also found among individuals who were no longer in working class positions and thus show that duration of experience matters, both as current and past experience.Study II: The study addresses the research gap of class-specificity in gender health inequality and seeks to further disentangle class and gender by studying gender gaps separately by class. The results show that there are class-specific gender gaps for both SRH and musculoskeletal pain, while the gender gap in psychiatric distress appears to be more general across class. Working conditions do not explain the between-class differences in gender gaps but contribute to specific gender differences in health within classes.Study III: The labour market has changed over time and has “upgraded” the class structure while at the same time the share of women in paid employment has increased. Therefore, female health may be increasingly influenced by occupational factors, such as working conditions. This study explores the class-specific nature of gender differences and investigates musculoskeletal pain and working conditions among employed men and women within classes during a time-period that spanned more than 30 years. There were class-specific gender gaps in health throughout the period. The gender gap has increased more, and is wider, among non-manual employees compared to the working classes. This development could not be explained by changes in working conditions.
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| 10. |
- Roslin, Sara, et al.
(författare)
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Reaction of 11C‐benzoyl chlorides with metalloid reagents: 11C‐labeling of benzyl alcohols, benzaldehydes, and phenylketones from [11C]CO
- 2018
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Ingår i: Journal of Labelled Compounds and Radiopharmaceuticals. - : Wiley. - 0362-4803 .- 1099-1344. ; 61:5, s. 447-454
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Tidskriftsartikel (refereegranskat)abstract
- In this article, we describe the carbonâ€11 (11C, t1/2 = 20.4 minutes) labeling of benzyl alcohols, benzaldehydes, and ketones using an efficient 2-€step synthesis in which 11C-€carbon monoxide is used in an initial palladium-€mediated reaction to produce 11C-€benzoyl chloride as a key intermediate. In the second step, the obtained 11C-€benzoyl chloride is further treated with a metalloid reagent to furnish the final 11C-€labeled product. Benzyl alcohols were obtained in moderated to high nonâ€isolated radiochemical yields (RCY, 35%-90%) with lithium aluminum hydride or lithium aluminum deuteride as metalloid reagent. Changing the metalloid reagent to either tributyltin hydride or sodium borohydride, allowed for the reliable syntheses of 11C-€benzaldehydes in RCYs ranging from 58% to 95%. Finally, sodium tetraphenylborate were utilized to obtain 11C-€phenyl ketones in high RCYs (77%-95%). The developed method provides a new and efficient route to 3 different classes of compounds starting from aryl iodides or aryl bromides.
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