| 1. |
|
|
| 2. |
- Klionsky, Daniel J., et al.
(author)
-
Guidelines for the use and interpretation of assays for monitoring autophagy
- 2012
-
In: Autophagy. - : Informa UK Limited. - 1554-8635 .- 1554-8627. ; 8:4, s. 445-544
-
Research review (peer-reviewed)abstract
- In 2008 we published the first set of guidelines for standardizing research in autophagy. Since then, research on this topic has continued to accelerate, and many new scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Accordingly, it is important to update these guidelines for monitoring autophagy in different organisms. Various reviews have described the range of assays that have been used for this purpose. Nevertheless, there continues to be confusion regarding acceptable methods to measure autophagy, especially in multicellular eukaryotes. A key point that needs to be emphasized is that there is a difference between measurements that monitor the numbers or volume of autophagic elements (e.g., autophagosomes or autolysosomes) at any stage of the autophagic process vs. those that measure flux through the autophagy pathway (i.e., the complete process); thus, a block in macroautophagy that results in autophagosome accumulation needs to be differentiated from stimuli that result in increased autophagic activity, defined as increased autophagy induction coupled with increased delivery to, and degradation within, lysosomes (in most higher eukaryotes and some protists such as Dictyostelium) or the vacuole (in plants and fungi). In other words, it is especially important that investigators new to the field understand that the appearance of more autophagosomes does not necessarily equate with more autophagy. In fact, in many cases, autophagosomes accumulate because of a block in trafficking to lysosomes without a concomitant change in autophagosome biogenesis, whereas an increase in autolysosomes may reflect a reduction in degradative activity. Here, we present a set of guidelines for the selection and interpretation of methods for use by investigators who aim to examine macroautophagy and related processes, as well as for reviewers who need to provide realistic and reasonable critiques of papers that are focused on these processes. These guidelines are not meant to be a formulaic set of rules, because the appropriate assays depend in part on the question being asked and the system being used. In addition, we emphasize that no individual assay is guaranteed to be the most appropriate one in every situation, and we strongly recommend the use of multiple assays to monitor autophagy. In these guidelines, we consider these various methods of assessing autophagy and what information can, or cannot, be obtained from them. Finally, by discussing the merits and limits of particular autophagy assays, we hope to encourage technical innovation in the field.
|
|
| 3. |
- Wilhelmson, Anna S K, et al.
(author)
-
Androgens regulate bone marrow B lymphopoiesis in male mice by targeting osteoblast-lineage cells.
- 2015
-
In: Endocrinology. - : The Endocrine Society. - 1945-7170 .- 0013-7227. ; 156:4, s. 1228-36
-
Journal article (peer-reviewed)abstract
- Testosterone has profound immune-modulatory actions, which may be important for the sexual dimorphism in immune-related disorders, such as autoimmune diseases. A well-known effect of androgens is inhibition of bone marrow B lymphopoiesis; however, a plausible target cell for this effect has not yet been presented. The aim of this study was to determine the target cell for androgen-mediated regulation of bone marrow B lymphopoiesis in males. We confirm higher number of bone marrow B cells in male mice with global inactivation of the androgen receptor (AR) and these global AR knockout (G-ARKO) mice had increased number of B cell precursors from the pro-B stage. Because osteoblast-lineage cells are known to support B lymphopoiesis at the pro-B stage, we investigated the effect on B lymphopoiesis in osteoblast-lineage cell-specific ARKO (O-ARKO) mice; O-ARKO mice had increased number of B cells in the bone marrow, and the number of B cell precursors was increased from the pro-B stage, demonstrating that O-ARKO mimics the bone marrow B lymphopoiesis pattern of G-ARKO mice. By contrast, O-ARKO mice displayed only minor changes in B cell numbers in the splenic compartment compared with G-ARKO. Further, O-ARKO mice had moderately reduced number of bone trabeculae in the vertebrae, whereas cortical bone was unaffected. In conclusion, androgens exert inhibitory effects on bone marrow B lymphopoiesis in males by targeting the AR in osteoblast-lineage cells. The identification of the likely target cell for androgen-mediated regulation of bone marrow B lymphopoiesis will contribute to elucidation of the mechanisms by which androgens modulate immune-related disorders.
|
|
| 4. |
- Aglago, Elom K., et al.
(author)
-
A Genetic Locus within the FMN1/GREM1 Gene Region Interacts with Body Mass Index in Colorectal Cancer Risk
- 2023
-
In: Cancer Research. - : American Association For Cancer Research (AACR). - 0008-5472 .- 1538-7445. ; 83:15, s. 2572-2583
-
Journal article (peer-reviewed)abstract
- Colorectal cancer risk can be impacted by genetic, environmental, and lifestyle factors, including diet and obesity. Gene-environment interactions (G × E) can provide biological insights into the effects of obesity on colorectal cancer risk. Here, we assessed potential genome-wide G × E interactions between body mass index (BMI) and common SNPs for colorectal cancer risk using data from 36,415 colorectal cancer cases and 48,451 controls from three international colorectal cancer consortia (CCFR, CORECT, and GECCO). The G × E tests included the conventional logistic regression using multiplicative terms (one degree of freedom, 1DF test), the two-step EDGE method, and the joint 3DF test, each of which is powerful for detecting G × E interactions under specific conditions. BMI was associated with higher colorectal cancer risk. The two-step approach revealed a statistically significant G×BMI interaction located within the Formin 1/Gremlin 1 (FMN1/GREM1) gene region (rs58349661). This SNP was also identified by the 3DF test, with a suggestive statistical significance in the 1DF test. Among participants with the CC genotype of rs58349661, overweight and obesity categories were associated with higher colorectal cancer risk, whereas null associations were observed across BMI categories in those with the TT genotype. Using data from three large international consortia, this study discovered a locus in the FMN1/GREM1 gene region that interacts with BMI on the association with colorectal cancer risk. Further studies should examine the potential mechanisms through which this locus modifies the etiologic link between obesity and colorectal cancer.SIGNIFICANCE: This gene-environment interaction analysis revealed a genetic locus in FMN1/GREM1 that interacts with body mass index in colorectal cancer risk, suggesting potential implications for precision prevention strategies.
|
|
| 5. |
- Bexelius, Maria, et al.
(author)
-
27 forskare : Så kan EU:s murar rivas
- 2015
-
In: Dagens samhälle. - : Sveriges kommuner och landsting. - 1652-6511. ; :20150923
-
Journal article (pop. science, debate, etc.)
|
|
| 6. |
|
|
| 7. |
- Fernandez-Rozadilla, Ceres, et al.
(author)
-
Deciphering colorectal cancer genetics through multi-omic analysis of 100,204 cases and 154,587 controls of European and east Asian ancestries
- 2023
-
In: Nature Genetics. - : Nature Publishing Group. - 1061-4036 .- 1546-1718. ; 55, s. 89-99
-
Journal article (peer-reviewed)abstract
- Colorectal cancer (CRC) is a leading cause of mortality worldwide. We conducted a genome-wide association study meta-analysis of 100,204 CRC cases and 154,587 controls of European and east Asian ancestry, identifying 205 independent risk associations, of which 50 were unreported. We performed integrative genomic, transcriptomic and methylomic analyses across large bowel mucosa and other tissues. Transcriptome- and methylome-wide association studies revealed an additional 53 risk associations. We identified 155 high-confidence effector genes functionally linked to CRC risk, many of which had no previously established role in CRC. These have multiple different functions and specifically indicate that variation in normal colorectal homeostasis, proliferation, cell adhesion, migration, immunity and microbial interactions determines CRC risk. Crosstissue analyses indicated that over a third of effector genes most probably act outside the colonic mucosa. Our findings provide insights into colorectal oncogenesis and highlight potential targets across tissues for new CRC treatment and chemoprevention strategies.
|
|
| 8. |
- Jones, Benedict C, et al.
(author)
-
To which world regions does the valence-dominance model of social perception apply?
- 2021
-
In: Nature Human Behaviour. - : Springer Science and Business Media LLC. - 2397-3374. ; 5:1, s. 159-169
-
Journal article (peer-reviewed)abstract
- Over the past 10 years, Oosterhof and Todorov's valence-dominance model has emerged as the most prominent account of how people evaluate faces on social dimensions. In this model, two dimensions (valence and dominance) underpin social judgements of faces. Because this model has primarily been developed and tested in Western regions, it is unclear whether these findings apply to other regions. We addressed this question by replicating Oosterhof and Todorov's methodology across 11 world regions, 41 countries and 11,570 participants. When we used Oosterhof and Todorov's original analysis strategy, the valence-dominance model generalized across regions. When we used an alternative methodology to allow for correlated dimensions, we observed much less generalization. Collectively, these results suggest that, while the valence-dominance model generalizes very well across regions when dimensions are forced to be orthogonal, regional differences are revealed when we use different extraction methods and correlate and rotate the dimension reduction solution. PROTOCOL REGISTRATION: The stage 1 protocol for this Registered Report was accepted in principle on 5 November 2018. The protocol, as accepted by the journal, can be found at https://doi.org/10.6084/m9.figshare.7611443.v1 .
|
|
| 9. |
- Jonsson Cornell, Anna, 1973-, et al.
(author)
-
Forska för en bättre värld
- 2018
-
In: Upsala nya tidning. - Uppsala. - 1104-0173.
-
Journal article (pop. science, debate, etc.)
|
|
| 10. |
|
|
| 11. |
|
|
| 12. |
- Tian, Yu, et al.
(author)
-
Genetic risk impacts the association of menopausal hormone therapy with colorectal cancer risk
- 2024
-
In: British Journal of Cancer. - : Springer Nature. - 0007-0920 .- 1532-1827. ; 130:10, s. 1687-1696
-
Journal article (peer-reviewed)abstract
- Background: Menopausal hormone therapy (MHT), a common treatment to relieve symptoms of menopause, is associated with a lower risk of colorectal cancer (CRC). To inform CRC risk prediction and MHT risk-benefit assessment, we aimed to evaluate the joint association of a polygenic risk score (PRS) for CRC and MHT on CRC risk.Methods: We used data from 28,486 postmenopausal women (11,519 cases and 16,967 controls) of European descent. A PRS based on 141 CRC-associated genetic variants was modeled as a categorical variable in quartiles. Multiplicative interaction between PRS and MHT use was evaluated using logistic regression. Additive interaction was measured using the relative excess risk due to interaction (RERI). 30-year cumulative risks of CRC for 50-year-old women according to MHT use and PRS were calculated.Results: The reduction in odds ratios by MHT use was larger in women within the highest quartile of PRS compared to that in women within the lowest quartile of PRS (p-value = 2.7 × 10−8). At the highest quartile of PRS, the 30-year CRC risk was statistically significantly lower for women taking any MHT than for women not taking any MHT, 3.7% (3.3%–4.0%) vs 6.1% (5.7%–6.5%) (difference 2.4%, P-value = 1.83 × 10−14); these differences were also statistically significant but smaller in magnitude in the lowest PRS quartile, 1.6% (1.4%–1.8%) vs 2.2% (1.9%–2.4%) (difference 0.6%, P-value = 1.01 × 10−3), indicating 4 times greater reduction in absolute risk associated with any MHT use in the highest compared to the lowest quartile of genetic CRC risk.Conclusions: MHT use has a greater impact on the reduction of CRC risk for women at higher genetic risk. These findings have implications for the development of risk prediction models for CRC and potentially for the consideration of genetic information in the risk-benefit assessment of MHT use.
|
|
| 13. |
- Tian, Yu, et al.
(author)
-
Genome-Wide Interaction Analysis of Genetic Variants With Menopausal Hormone Therapy for Colorectal Cancer Risk
- 2022
-
In: Journal of the National Cancer Institute. - : Oxford University Press. - 0027-8874 .- 1460-2105. ; 114:8, s. 1135-1148
-
Journal article (peer-reviewed)abstract
- BACKGROUND: The use of menopausal hormone therapy (MHT) may interact with genetic variants to influence colorectal cancer (CRC) risk. METHODS: We conducted a genome-wide, gene-environment interaction between single nucleotide polymorphisms and the use of any MHT, estrogen only, and combined estrogen-progestogen therapy with CRC risk, among 28 486 postmenopausal women (11 519 CRC patients and 16 967 participants without CRC) from 38 studies, using logistic regression, 2-step method, and 2- or 3-degree-of-freedom joint test. A set-based score test was applied for rare genetic variants. RESULTS: The use of any MHT, estrogen only and estrogen-progestogen were associated with a reduced CRC risk (odds ratio [OR] = 0.71, 95% confidence interval [CI] = 0.64 to 0.78; OR = 0.65, 95% CI = 0.53 to 0.79; and OR = 0.73, 95% CI = 0.59 to 0.90, respectively). The 2-step method identified a statistically significant interaction between a GRIN2B variant rs117868593 and MHT use, whereby MHT-associated CRC risk was statistically significantly reduced in women with the GG genotype (OR = 0.68, 95% CI = 0.64 to 0.72) but not within strata of GC or CC genotypes. A statistically significant interaction between a DCBLD1 intronic variant at 6q22.1 (rs10782186) and MHT use was identified by the 2-degree-of-freedom joint test. The MHT-associated CRC risk was reduced with increasing number of rs10782186-C alleles, showing odds ratios of 0.78 (95% CI = 0.70 to 0.87) for TT, 0.68 (95% CI = 0.63 to 0.73) for TC, and 0.66 (95% CI = 0.60 to 0.74) for CC genotypes. In addition, 5 genes in rare variant analysis showed suggestive interactions with MHT (2-sided P < 1.2 × 10-4). CONCLUSION: Genetic variants that modify the association between MHT and CRC risk were identified, offering new insights into pathways of CRC carcinogenesis and potential mechanisms involved.
|
|
| 14. |
|
|
| 15. |
|
|
| 16. |
|
|
| 17. |
|
|
| 18. |
- Almqvist, Gustaf, et al.
(author)
-
Report of the Benchmark Workshop on Baltic Cod Stocks (WKBALTCOD)
- 2015
-
Reports (other academic/artistic)abstract
- The ICES Benchmark Workshop on Baltic Cod Stocks (WKBALTCOD), chaired by External Chair Jean-Jacques Maguire, Canada and ICES Chair Marie Storr-Paulsen, Denmark, and attended by two invited external experts Verena Trenkel, France and Meaghan Bryan, USA met in Rostock, Germany, 2–6 March 2015 with 39 participants and six countries represented. The objective of WKBALTCOD was to evaluate the appropriateness of data and methods to determine stock status and investigate meth-ods appropriate to use in the single-stock assessment for the cod stock in SD 22–24 and cod in SD 25–32 in the Baltic. Participants in the workshop were a large group with diverse backgrounds representing the industry, fisheries, NGOs, managers and scientists.The single-stock analytic assessment of the eastern Baltic stock was not accepted by the assessment working group (WGBFAS) in 2014 due to severe problems with the input data. The advice for the eastern Baltic cod was, therefore, based on the ICES approach for data-limited stocks. As an outcome ICES decided to establish a bench-mark for both cod stocks and to scope an integrated assessment for the Baltic cod stocks. The first meeting (WKSIBCA) was therefore meant to introduce the interces-sional work conducted since the assessment working group in April 2014, and to reach some conclusions on how to proceed both in the short term (Benchmark in March 2015) and longer term (2–3 years) and was seen as a data compilation work-shop, there is produced a separate report from this workshop. The WKBALTCOD was the 2nd meeting in the benchmark process and was intended to come up with a final stock assessment method, stock annex and input data for both stocks. As it was not possible to reach conclusive decision on the final model to be used for the east Baltic cod stock during the benchmark meeting and as more work on the preferable models was needed, it was decided by the ACOM leadership to prolong the bench-mark process until the assessment working group meeting in April 2015. This deci-sion has led to a relatively long process partly mixed with the assessment working group WGBFAS.It became clear during the benchmark process that although large effort has been put into explaining the underlying processes leading to the changes in the Baltic ecosys-tem, there is still some lack of understanding of the present situation in the eastern Baltic cod stock. Therefore, it was not possible to reach firm conclusions on the final model to be used and therefore not possible to set reference points. It was decided to continue to explore the most promising models and to continue to improve the input data until the assessment working group started in April.The main challenges still to be solved for the Eastern Baltic cod stock is the quantifi-cation of increased natural mortality and decrease in growth. Through several presentations during the workshop (both WKSIBCA and WKBALTCOD) it became clear that natural mortality very likely has increased in later years, due to decreased condition and increased parasite infection. A decrease in growth also seems plausible duo to a decrease in condition and/or selectivity-induced mortality of the largest in-dividuals. However, as none of these parameters are easily estimated, especially with the severe ageing problems, different model assumptions made the output very shaky.For the western Baltic cod, stock identification issues were examined in area SD 24, the intermediate area: based on otolith characteristics and genetics. Due to the results showing a large proportion of east cod in this area, it was decided to split the catch2 | ICES WKBALTCOD REPORT 2015and survey from SD 24 into either the western or eastern Baltic cod stock. It was pos-sible to derive proportions of eastern and western cod in SD 24 back to the mid-1990s.For the western Baltic cod stock a modelled survey indices was included in the as-sessment covering the western part of SD 24 and Area 22+23 and based on a smoothed ALK.Both cod stocks have in the past used commercial tuning fleet to have a better cov-ered of older age groups. It was decided to abound this time-series duo quality issues such as a limited coverage and problems with technical creeping.WKBALTCOD was not able to explore and define reference points for the Western Baltic cod stock during the meeting due to time constraints, but these were calculated and decided by correspondence after the meeting. The recent protocols on estimation procedures developed by WKMSYREF3 for stocks with a full analytical assessment and for data-limited stocks served as objective guidelines to obtain reference point estimates.
|
|
| 19. |
- Andersson, Sofia E M, 1979, et al.
(author)
-
Collagen epitope expression on B cells is sufficient to confer tolerance to collagen-induced arthritis
- 2016
-
In: Arthritis Research & Therapy. - : Springer Science and Business Media LLC. - 1478-6362. ; 18
-
Journal article (peer-reviewed)abstract
- Background: The mechanisms underlying tolerance induction and maintenance in autoimmune arthritis remain elusive. In a mouse model of rheumatoid arthritis, collagen type II (CII)-induced arthritis, we explore the contribution of B cells to antigen-specific tolerance. Methods: To generate expression of the CII-peptide specifically on B-cell major histocompatibility complex type II, lentiviral-based gene therapy including a B-cell-specific Igk promoter was used. Results: Presentation of the CII-peptide on B cells significantly reduced the frequency and severity of arthritis as well as the serum levels of CII -specific IgG antibodies. Further, both frequency and suppressive function of regulatory T cells were increased in tolerized mice. Adoptive transfer of regulatory T cells from tolerized mice to naive mice ameliorated the development of CII-induced arthritis. Conclusion: Our data suggest that endogenous presentation of the CII-peptide on B cells is one of the key contributors to arthritis tolerance induction and maintenance.
|
|
| 20. |
- Babulal, Ganesh M, et al.
(author)
-
Perspectives on ethnic and racial disparities in Alzheimer's disease and related dementias: Update and areas of immediate need.
- 2019
-
In: Alzheimer's & Dementia. - : Wiley. - 1552-5260 .- 1552-5279. ; 15:2, s. 292-312
-
Journal article (peer-reviewed)abstract
- Alzheimer's disease and related dementias (ADRDs) are a global crisis facing the aging population and society as a whole. With the numbers of people with ADRDs predicted to rise dramatically across the world, the scientific community can no longer neglect the need for research focusing on ADRDs among underrepresented ethnoracial diverse groups. The Alzheimer's Association International Society to Advance Alzheimer's Research and Treatment (ISTAART; alz.org/ISTAART) comprises a number of professional interest areas (PIAs), each focusing on a major scientific area associated with ADRDs. We leverage the expertise of the existing international cadre of ISTAART scientists and experts to synthesize a cross-PIA white paper that provides both a concise "state-of-the-science" report of ethnoracial factors across PIA foci and updated recommendations to address immediate needs to advance ADRD science across ethnoracial populations.
|
|
| 21. |
- Beskow, Anna, 1972-
(author)
-
Genetic Risk Factors for Cervical Carcinoma in situ
- 2003
-
Doctoral thesis (other academic/artistic)abstract
- Oncogenic human papillomaviruses (HPVs) are implicated in 99.7 % of cervical cancer cases but require the co-operation of other factors. To investigate potential genetic risk factors we have typed the HLA class II DRB1 and DQB1 loci in 478 women diagnosed with cervical carcinoma in situ and in 608 age-matched controls. Quantitative measurements of HPV 16, HPV 18/45 and HPV 31 were obtained. The DRB1*1501 and DQB1*0602 alleles were found to increase the risk of HPV 16 infection. Carriers of DRB1*1501 and DQB1*0602 were also shown to have an increased risk of a higher viral load compared to non-carriers. The DRB1*1301 and DQB1*0603 alleles were found to protect from HPV 18/45 and 31 infections as well as resulting in a lower viral load in carriers compared to non-carriers. Women with a high HPV 16, 18/45 or 31 viral load were more prone to long-term infections and women with a low HPV 16 viral load were more prone to short-term infections. Carriers of DRB1*1501 and DQB1*0602 alleles were also shown to have an increased risk of long-term infections compared to short-term infections. We also tested if an HPV susceptibility locus found for epidermodysplasia verruciformis (EV) was also linked to HPV susceptibility in cervical cancer. We did not find any linkage to this locus in a set of 77 families, each with at least three cases diagnosed with cervical carcinoma in situ. Other potential risk factors tested were HPV 16 E6 variants together with a p53 codon 72 polymorphism and HLA class II alleles. We found an association between the E6 L83V variant and the HLA DR4-DQ3 haplotype, as well as an increased frequency of Arg homozygosity of p53 in women infected with the L83V variant. These results show that alleles at HLA class II loci represents risk factors for persistent HPV infection and thereby also contribute to the risk of development of cervical carcinoma in situ.
|
|
| 22. |
- Bouras, Emmanouil, et al.
(author)
-
Genome-wide interaction analysis of folate for colorectal cancer risk
- 2023
-
In: American Journal of Clinical Nutrition. - : Elsevier. - 0002-9165 .- 1938-3207. ; 118:5, s. 881-891
-
Journal article (peer-reviewed)abstract
- Background: Epidemiological and experimental evidence suggests that higher folate intake is associated with decreased colorectal cancer (CRC) risk; however, the mechanisms underlying this relationship are not fully understood. Genetic variation that may have a direct or indirect impact on folate metabolism can provide insights into folate's role in CRC.Objectives: Our aim was to perform a genome-wide interaction analysis to identify genetic variants that may modify the association of folate on CRC risk.Methods: We applied traditional case-control logistic regression, joint 3-degree of freedom, and a 2-step weighted hypothesis approach to test the interactions of common variants (allele frequency >1%) across the genome and dietary folate, folic acid supplement use, and total folate in relation to risk of CRC in 30,550 cases and 42,336 controls from 51 studies from 3 genetic consortia (CCFR, CORECT, GECCO).Results: Inverse associations of dietary, total folate, and folic acid supplement with CRC were found (odds ratio [OR]: 0.93; 95% confidence interval [CI]: 0.90, 0.96; and 0.91; 95% CI: 0.89, 0.94 per quartile higher intake, and 0.82 (95% CI: 0.78, 0.88) for users compared with nonusers, respectively). Interactions (P-interaction < 5×10-8) of folic acid supplement and variants in the 3p25.2 locus (in the region of Synapsin II [SYN2]/tissue inhibitor of metalloproteinase 4 [TIMP4]) were found using traditional interaction analysis, with variant rs150924902 (located upstream to SYN2) showing the strongest interaction. In stratified analyses by rs150924902 genotypes, folate supplementation was associated with decreased CRC risk among those carrying the TT genotype (OR: 0.82; 95% CI: 0.79, 0.86) but increased CRC risk among those carrying the TA genotype (OR: 1.63; 95% CI: 1.29, 2.05), suggesting a qualitative interaction (P-interaction = 1.4×10-8). No interactions were observed for dietary and total folate.Conclusions: Variation in 3p25.2 locus may modify the association of folate supplement with CRC risk. Experimental studies and studies incorporating other relevant omics data are warranted to validate this finding.
|
|
| 23. |
- Carreras-Torres, Robert, et al.
(author)
-
Genome-wide interaction study with smoking for colorectal cancer risk identifies novel genetic loci related to tumor suppression, inflammation, and immune response
- 2023
-
In: Cancer Epidemiology, Biomarkers and Prevention. - : American association for cancer research. - 1055-9965 .- 1538-7755. ; 32:3, s. 315-328
-
Journal article (peer-reviewed)abstract
- BACKGROUND: Tobacco smoking is an established risk factor for colorectal cancer. However, genetically defined population subgroups may have increased susceptibility to smoking-related effects on colorectal cancer.METHODS: A genome-wide interaction scan was performed including 33,756 colorectal cancer cases and 44,346 controls from three genetic consortia.RESULTS: Evidence of an interaction was observed between smoking status (ever vs. never smokers) and a locus on 3p12.1 (rs9880919, P = 4.58 × 10-8), with higher associated risk in subjects carrying the GG genotype [OR, 1.25; 95% confidence interval (CI), 1.20-1.30] compared with the other genotypes (OR <1.17 for GA and AA). Among ever smokers, we observed interactions between smoking intensity (increase in 10 cigarettes smoked per day) and two loci on 6p21.33 (rs4151657, P = 1.72 × 10-8) and 8q24.23 (rs7005722, P = 2.88 × 10-8). Subjects carrying the rs4151657 TT genotype showed higher risk (OR, 1.12; 95% CI, 1.09-1.16) compared with the other genotypes (OR <1.06 for TC and CC). Similarly, higher risk was observed among subjects carrying the rs7005722 AA genotype (OR, 1.17; 95% CI, 1.07-1.28) compared with the other genotypes (OR <1.13 for AC and CC). Functional annotation revealed that SNPs in 3p12.1 and 6p21.33 loci were located in regulatory regions, and were associated with expression levels of nearby genes. Genetic models predicting gene expression revealed that smoking parameters were associated with lower colorectal cancer risk with higher expression levels of CADM2 (3p12.1) and ATF6B (6p21.33).CONCLUSIONS: Our study identified novel genetic loci that may modulate the risk for colorectal cancer of smoking status and intensity, linked to tumor suppression and immune response.IMPACT: These findings can guide potential prevention treatments.
|
|
| 24. |
- Dane, Louise, 1986-
(author)
-
Den reglerade invandringen och barnets bästa : Barns rätt till familjeliv och privatliv enligt barnkonventionen, Europakonventionen, EU-rätten och svensk utlänningslagstiftning
- 2019
-
Doctoral thesis (other academic/artistic)abstract
- This thesis analyses the principle of the best interests of the child and the right to private and family life in relation to the societal interest of controlling immigration. The aim of the thesis is to contribute to ensuring more predictable and transparent legislation and decision-making.States, generally, have the right to control immigration. At the same time, a child’s right to family and private life is a human right – regulated, for example, by the UN Convention of the Rights of the Child, the European Convention on Human Rights and the EU Charter of Fundamental Rights. This means that states can only restrict these rights when such interference is justified. In migration cases concerning private and family life, an assessment therefore must be made as to whether a decision to refuse residence is proportional. When a child is affected by such a decision, the child's best interests must be carefully assessed and taken into consideration. This thesis examines what is legally required of a correct decision in migration cases concerning a child’s right to private and family life. Particular attention is given to those requirements imposed on lawmakers and legal actors by the public law principles of legality, objectivity and proportionality, as well as the duty to give reasoned decisions. This thesis charts the development and foundations of Swedish migration law including those requirements arising from EU and public international law. The focus thereafter is more specifically on the assessments made balancing the interests of children's rights and immigration control.Whether a restriction of the right to private and family life is proportionate is determined by the specific circumstances in the individual case. However, the research conducted demonstrates that there is a lack of guidance concerning which circumstances Swedish legal actors can and should consider, as well as the weight that should be attributed to the considered circumstances. The interest of immigration control is particularly ambiguous. The thesis identifies four types of circumstances that the Swedish lawmaker appears to suggest legal actors consider within this interest; (a) public order and security, (b) maintenance and enforcement of immigration control, (c) national economic well-being (including number of migrants), and (d) protection of the rights and freedoms of others.Lack of clear guidance is problematic, particularly in light of the principles of legality, objectivity and proportionality, as the outcomes of cases depend on what individual legal actors choose to consider. Vague guidance on what constitutes relevant circumstances may also contribute to the problem of poorly formulated decisions as identified in previous research. In order to increase the probability of legal actors rendering more correct decisions – on the basis of applicable law – a five-step model is presented: (1) identifying private and/or family life (2) identifying the child's best interests (3) identifying the underlying motivations linked to the interest of immigration control (4) listing the arguments for and against granting residence in Sweden and (5) determining which interests should prevail.The thesis concludes with a number of recommendations aimed mainly at lawmakers that could contribute to strengthening children's rights and increasing adherence to the rule of law in migration cases concerning children's right to private and family life.
|
|
| 25. |
- Dane, Louise, et al.
(author)
-
Dubbla budskap om barns rättigheter
- 2016
-
In: Svenska Dagbladet - Debatt. - 1101-2412. ; :2016-03-10
-
Journal article (other academic/artistic)abstract
- Flera förslag på senare tid går ut på att vissa grupper av barn som vistas i Sverige ska vägras sina rättigheter. Men när det gäller barn finns i enlighet med barnkonventionen inte utrymme att ge olika rättigheter. Det skriver flera jurister gemensamt.
|
|
| 26. |
|
|
| 27. |
- Delios, A., et al.
(author)
-
Examining the generalizability of research findings from archival data
- 2022
-
In: Proceedings of the National Academy of Sciences of the United States of America. - : Proceedings of the National Academy of Sciences. - 0027-8424 .- 1091-6490. ; 119:30
-
Journal article (peer-reviewed)abstract
- This initiative examined systematically the extent to which a large set of archival research findings generalizes across contexts. We repeated the key analyses for 29 original strategic management effects in the same context (direct reproduction) as well as in 52 novel time periods and geographies; 45% of the reproductions returned results matching the original reports together with 55% of tests in different spans of years and 40% of tests in novel geographies. Some original findings were associated with multiple new tests. Reproducibility was the best predictor of generalizability-for the findings that proved directly reproducible, 84% emerged in other available time periods and 57% emerged in other geographies. Overall, only limited empirical evidence emerged for context sensitivity. In a forecasting survey, independent scientists were able to anticipate which effects would find support in tests in new samples.
|
|
| 28. |
- Dickstein, Yaakov, et al.
(author)
-
Treatment Outcomes of Colistin- and Carbapenem-resistant Acinetobacter baumannii Infections : An Exploratory Subgroup Analysis of a Randomized Clinical Trial
- 2019
-
In: Clinical Infectious Diseases. - : OXFORD UNIV PRESS INC. - 1058-4838 .- 1537-6591. ; 69:5, s. 769-776
-
Journal article (peer-reviewed)abstract
- Background We evaluated the association between mortality and colistin resistance in Acinetobacter baumannii infections and the interaction with antibiotic therapy. Methods This is a secondary analysis of a randomized controlled trial of patients with carbapenem-resistant gram-negative bacterial infections treated with colistin or colistin-meropenem combination. We evaluated patients with infection caused by carbapenem-resistant A. baumannii (CRAB) identified as colistin susceptible (CoS) at the time of treatment and compared patients in which the isolate was confirmed as CoS with those whose isolates were retrospectively identified as colistin resistant (CoR) when tested by broth microdilution (BMD). The primary outcome was 28-day mortality. Results Data were available for 266 patients (214 CoS and 52 CoR isolates). Patients with CoR isolates had higher baseline functional capacity and lower rates of mechanical ventilation than patients with CoS isolates. All-cause 28-day mortality was 42.3% (22/52) among patients with CoR strains and 52.8% (113/214) among patients with CoS isolates (P = .174). After adjusting for variables associated with mortality, the mortality rate was lower among patients with CoR isolates (odds ratio [OR], 0.285 [95% confidence interval {CI}, .118-.686]). This difference was associated with treatment arm: Mortality rates among patients with CoR isolates were higher in those randomized to colistin-meropenem combination therapy compared to colistin monotherapy (OR, 3.065 [95% CI, 1.021-9.202]). Conclusions Colistin resistance determined by BMD was associated with lower mortality among patients with severe CRAB infections. Among patients with CoR isolates, colistin monotherapy was associated with a better outcome compared to colistin-meropenem combination therapy.
|
|
| 29. |
- Drevin, Jennifer, et al.
(author)
-
Adverse childhood experiences influence development of pain during pregnancy.
- 2015
-
In: Acta Obstetricia et Gynecologica Scandinavica. - : Wiley. - 0001-6349 .- 1600-0412. ; 94:8, s. 840-846
-
Journal article (peer-reviewed)abstract
- OBJECTIVE: To investigate the association between adverse childhood experiences (ACE) and pain with onset during pregnancy.DESIGN: Cross-sectional study.SETTING: Eighteen antenatal clinics in southern Mid-Sweden.SAMPLE: Of 293 women invited to participate, 232 (79%) women agreed to participate in early pregnancy and were assessed in late pregnancy.METHODS: Questionnaires were distributed in early and late pregnancy. The questionnaires sought information on socio-demography, ACE, pain location by pain drawing and pain intensity by visual analogue scales. Distribution of pain was coded in 41 predetermined areas.MAIN OUTCOME MEASURES: Pain in third trimester with onset during present pregnancy: intensity, location and number of pain locations.RESULTS: In late pregnancy, 62% of the women reported any ACE and 72% reported any pain location with onset during the present pregnancy. Among women reporting any ACE the median pain intensity was higher compared with women without such an experience (p = 0.01). The accumulated ACE displayed a positive association with the number of reported pain locations in late pregnancy (rs = 0.19, p = 0.02). This association remained significant after adjusting for background factors in multiple regression analysis (p = 0.01). When ACE was dichotomized the prevalence of pain did not differ between women with and without ACE. The subgroup of women reporting physical abuse as a child reported a higher prevalence of sacral and pelvic pain (p = 0.0003 and p = 0.02, respectively).CONCLUSIONS: Adverse childhood experiences were associated with higher pain intensities and larger pain distributions in late pregnancy, which are risk factors for transition to chronic pain postpartum.
|
|
| 30. |
- Drew, David A., et al.
(author)
-
Two genome-wide interaction loci modify the association of nonsteroidal anti-inflammatory drugs with colorectal cancer
- 2024
-
In: Science Advances. - : American Association for the Advancement of Science (AAAS). - 2375-2548. ; 10:22
-
Journal article (peer-reviewed)abstract
- Regular, long-term aspirin use may act synergistically with genetic variants, particularly those in mechanistically relevant pathways, to confer a protective effect on colorectal cancer (CRC) risk. We leveraged pooled data from 52 clinical trial, cohort, and case-control studies that included 30,806 CRC cases and 41,861 controls of European ancestry to conduct a genome-wide interaction scan between regular aspirin/nonsteroidal anti-inflammatory drug (NSAID) use and imputed genetic variants. After adjusting for multiple comparisons, we identified statistically significant interactions between regular aspirin/NSAID use and variants in 6q24.1 (top hit rs72833769), which has evidence of influencing expression of TBC1D7 (a subunit of the TSC1-TSC2 complex, a key regulator of MTOR activity), and variants in 5p13.1 (top hit rs350047), which is associated with expression of PTGER4 (codes a cell surface receptor directly involved in the mode of action of aspirin). Genetic variants with functional impact may modulate the chemopreventive effect of regular aspirin use, and our study identifies putative previously unidentified targets for additional mechanistic interrogation.
|
|
| 31. |
- Eriksson, Anna-Karin, 1979-
(author)
-
Global history or inter|nationalist discourse!? : Unsettling the 'comfort women' issue
- 2022
-
Doctoral thesis (other academic/artistic)abstract
- Survivors of the ‘comfort’ system, the state-sponsored regime of military sexual exploitation and a core institution in the expansion of the empire of Japan from 1932 to 1945, continue to go unrecognised almost 80 years past 1945 and 30 years after the breakthrough by human rights activists in 1991. That such a brutal regime of sexual exploitation remains unrecognised by the state is remarkable and merits attention. In this thesis, I suggest that the ‘comfort women’ issue remains stuck in a deadlock that freezes it in the inter-state framing of a status quo. As a result the comfort women, the survivors and supposed protagonists, are rendered as mere tiles in a series of inter-state conflicts between the State of Japan and its neighbours in Northeast Asia as one of the fiercest battlegrounds in this region’s ‘history wars’. My purpose in the thesis is to offer possibilities to rethink the comfort women issue beyond this deadlock. To this end, I (1) identify the dynamics that sustain and reify the deadlock (Paper 1 and Paper 2) and (2) unsettle these dynamics (Paper 3 and Paper 4).
|
|
| 32. |
- Essén, Anna, et al.
(author)
-
Health app policy: international comparison of nine countries' approaches
- 2022
-
In: npj Digital Medicine. - : Springer Nature. - 2398-6352 .- 2398-6352. ; 5:1
-
Journal article (peer-reviewed)abstract
- An abundant and growing supply of digital health applications (apps) exists in the commercial tech-sector, which can be bewildering for clinicians, patients, and payers. A growing challenge for the health care system is therefore to facilitate the identification of safe and effective apps for health care practitioners and patients to generate the most health benefit as well as guide payer coverage decisions. Nearly all developed countries are attempting to define policy frameworks to improve decision-making, patient care, and health outcomes in this context. This study compares the national policy approaches currently in development/use for health apps in nine countries. We used secondary data, combined with a detailed review of policy and regulatory documents, and interviews with key individuals and experts in the field of digital health policy to collect data about implemented and planned policies and initiatives. We found that most approaches aim for centralized pipelines for health app approvals, although some countries are adding decentralized elements. While the countries studied are taking diverse paths, there is nevertheless broad, international convergence in terms of requirements in the areas of transparency, health content, interoperability, and privacy and security. The sheer number of apps on the market in most countries represents a challenge for clinicians and patients. Our analyses of the relevant policies identified challenges in areas such as reimbursement, safety, and privacy and suggest that more regulatory work is needed in the areas of operationalization, implementation and international transferability of approvals. Cross-national efforts are needed around regulation and for countries to realize the benefits of these technologies.
|
|
| 33. |
|
|
| 34. |
|
|
| 35. |
- Hammerstein, Erica, et al.
(author)
-
The Final Season Reimagined : 30 Tidal Disruption Events from the ZTF-I Survey
- 2023
-
In: Astrophysical Journal. - : American Astronomical Society. - 0004-637X .- 1538-4357. ; 942:1
-
Journal article (peer-reviewed)abstract
- Tidal disruption events (TDEs) offer a unique way to study dormant black holes. While the number of observed TDEs has grown thanks to the emergence of wide-field surveys in the past few decades, questions regarding the nature of the observed optical, UV, and X-ray emission remain. We present a uniformly selected sample of 30 spectroscopically classified TDEs from the Zwicky Transient Facility Phase I survey operations with follow-up Swift UV and X-ray observations. Through our investigation into correlations between light-curve properties, we recover a shallow positive correlation between the peak bolometric luminosity and decay timescales. We introduce a new spectroscopic class of TDE, TDE-featureless, which are characterized by featureless optical spectra. The new TDE-featureless class shows larger peak bolometric luminosities, peak blackbody temperatures, and peak blackbody radii. We examine the differences between the X-ray bright and X-ray faint populations of TDEs in this sample, finding that X-ray bright TDEs show higher peak blackbody luminosities than the X-ray faint subsample. This sample of optically selected TDEs is the largest sample of TDEs from a single survey yet, and the systematic discovery, classification, and follow-up of this sample allows for robust characterization of TDE properties, an important stepping stone looking forward toward the Rubin era.
|
|
| 36. |
|
|
| 37. |
- Ren, Weicheng, et al.
(author)
-
Surrogate light chain is required for central and peripheral B-cell tolerance and inhibits anti-DNA antibody production by marginal zone B cells
- 2015
-
In: European Journal of Immunology. - : Wiley. - 0014-2980 .- 1521-4141. ; 45:4, s. 1228-1237
-
Journal article (peer-reviewed)abstract
- Selection of the primary antibody repertoire takes place in pro-/pre-B cells, and subsequently in immature and transitional B cells. At the first checkpoint, μ heavy (μH) chains assemble with surrogate light (SL) chain into a precursor B-cell receptor. In mice lacking SL chain, μH chain selection is impaired, and serum autoantibody levels are elevated. However, whether the development of autoantibody-producing cells is due to an inability of the resultant B-cell receptors to induce central and/or peripheral B-cell tolerance or other factors is unknown. Here, we show that receptor editing is defective, and that a higher proportion of BM immature B cells are prone to undergoing apoptosis. Furthermore, transitional B cells are also more prone to undergoing apoptosis, with a stronger selection pressure to enter the follicular B-cell pool. Those that enter the marginal zone (MZ) B-cell pool escape selection and survive, possibly due to the B-lymphopenia and elevated levels of B-cell activating factor. Moreover, the MZ B cells are responsible for the elevated IgM anti-dsDNA antibody levels detected in these mice. Thus, the SL chain is required for central and peripheral B-cell tolerance and inhibits anti-DNA antibody production by MZ B cells.
|
|
| 38. |
|
|
| 39. |
- Salih Joelsson, Lana, 1969-, et al.
(author)
-
Anxiety and depression symptoms among sub-fertile women, women pregnant after infertility treatment, and naturally pregnant women
- 2017
-
In: European psychiatry. - : Cambridge University Press (CUP). - 0924-9338 .- 1778-3585. ; 45, s. 212-219
-
Journal article (peer-reviewed)abstract
- BackgroundInfertility has been associated with psychological distress, but whether these symptoms persist after achieving pregnancy via assisted reproductive technology (ART) remains unclear. We compared the prevalence of anxiety and depressive symptoms between women seeking for infertility treatment and women who conceived after ART or naturally.MethodsFour hundred and sixty-eight sub-fertile non-pregnant women, 2972 naturally pregnant women and 143 women pregnant after ART completed a questionnaire in this cross-sectional study. The Anxiety subscale of the Hospital Anxiety and Depression Scale (HADS-A≥8) and Edinburgh Postnatal Depression Scale (EPDS≥12) were used for assessing anxiety and depressive symptoms, respectively. Multivariate Poisson regression models with robust variance were applied to explore associations with anxiety and depressive symptoms.ResultsThe prevalence of anxiety and depressive symptoms among sub-fertile, non-pregnant women (57.6% and 15.7%, respectively) were significantly higher compared to women pregnant after ART (21.1% and 8.5%, respectively) and naturally pregnant women (18.8% and 10.3%, respectively). History of psychiatric diagnosis was identified as an independent risk factor for both anxiety and depressive symptoms. The presence of at least one unhealthy lifestyle behavior (daily tobacco smoking, weekly alcohol consumption, BMI≥25, and regular physical exercise < 2 h/week) was also associated with anxiety (Prevalence Ratio, PR: 1.24; 95%CI: 1.09–1.40) and depressive symptoms (PR: 1.25; 95%CI: 1.04–1.49).ConclusionsWomen pregnant after ART showed no difference in anxiety and depressive symptoms compared to naturally pregnant women. However, early psychological counseling and management of unhealthy lifestyle behaviors for sub-fertile women may be advisable, particularly for women with a previous history of psychiatric diagnosis.
|
|
| 40. |
- Salter, Mark, et al.
(author)
-
Race and racism in critical security studies
- 2021
-
In: Security Dialogue. - : SAGE Publications. - 0967-0106 .- 1460-3640. ; 52:1 (suppl), s. 3-7
-
Journal article (other academic/artistic)abstract
- In the current moment, we are witnessing a resurgent political urgency around demands to overthrow the inequities that are entrenched in oppressive structural formations such as racism and colonialism. Debates about race and racism are also unfolding in academia. While there has been a long tradition of speaking plainly about race within international relations (Doty, 1993; Grovogui, 2001), the past decade has seen a re-engagement not just with race as an analytical category but also with racism (Anievas et al., 2015; Muppidi, 2018; Rutazibwa, 2016; Vitalis, 2015), frequently articulated in terms of, or alongside calls for, the decolonization of academia.
|
|
| 41. |
- Schmit, Stephanie L, et al.
(author)
-
Novel Common Genetic Susceptibility Loci for Colorectal Cancer.
- 2019
-
In: Journal of the National Cancer Institute. - : Oxford University Press (OUP). - 0027-8874 .- 1460-2105. ; 111:2, s. 146-157
-
Journal article (peer-reviewed)abstract
- Background: Previous genome-wide association studies (GWAS) have identified 42 loci (P < 5 × 10-8) associated with risk of colorectal cancer (CRC). Expanded consortium efforts facilitating the discovery of additional susceptibility loci may capture unexplained familial risk.Methods: We conducted a GWAS in European descent CRC cases and control subjects using a discovery-replication design, followed by examination of novel findings in a multiethnic sample (cumulative n = 163 315). In the discovery stage (36 948 case subjects/30 864 control subjects), we identified genetic variants with a minor allele frequency of 1% or greater associated with risk of CRC using logistic regression followed by a fixed-effects inverse variance weighted meta-analysis. All novel independent variants reaching genome-wide statistical significance (two-sided P < 5 × 10-8) were tested for replication in separate European ancestry samples (12 952 case subjects/48 383 control subjects). Next, we examined the generalizability of discovered variants in East Asians, African Americans, and Hispanics (12 085 case subjects/22 083 control subjects). Finally, we examined the contributions of novel risk variants to familial relative risk and examined the prediction capabilities of a polygenic risk score. All statistical tests were two-sided.Results: The discovery GWAS identified 11 variants associated with CRC at P < 5 × 10-8, of which nine (at 4q22.2/5p15.33/5p13.1/6p21.31/6p12.1/10q11.23/12q24.21/16q24.1/20q13.13) independently replicated at a P value of less than .05. Multiethnic follow-up supported the generalizability of discovery findings. These results demonstrated a 14.7% increase in familial relative risk explained by common risk alleles from 10.3% (95% confidence interval [CI] = 7.9% to 13.7%; known variants) to 11.9% (95% CI = 9.2% to 15.5%; known and novel variants). A polygenic risk score identified 4.3% of the population at an odds ratio for developing CRC of at least 2.0.Conclusions: This study provides insight into the architecture of common genetic variation contributing to CRC etiology and improves risk prediction for individualized screening.
|
|
| 42. |
|
|
| 43. |
- Stavrianakis, Anna, et al.
(author)
-
Militarism and security: Dialogue, possibilities and limits
- 2018
-
In: Security Dialogue. - : SAGE Publications. - 0967-0106 .- 1460-3640. ; 49:1-2, s. 3-18
-
Journal article (peer-reviewed)abstract
- While attention to security has grown exponentially over the last few decades, militarism – the preparation for and normalization and legitimation of war – has not received the widespread and sustained focus it warrants in mainstream or critical circles. Rather than stake a claim for one concept over the other, however, this article – and the special issue to which it serves as an introduction – asks how we are to understand the relationship between security and militarism, both as analytical tools and as objects of analysis. We examine, first, what analytical and political work militarism and security do as concepts, and how they can be mobilized methodologically; second, what the possibilities are of fruitful exchange between knowledges produced about these concepts or practices; and, third, what the limits are of militarism and security. In the process, we address the shifts in the world that international relations and its related subfields study; shifts in the institutional framing and materiality of fields and subfields of research; and shifts in how international relations studies the world. Read together, the contributions to the special issue make the case for a reinvigorated focus on the mutual co-constitution of militarism and security.
|
|
| 44. |
- Stein, Robert, et al.
(author)
-
A tidal disruption event coincident with a high-energy neutrino
- 2021
-
In: Nature Astronomy. - : Springer Science and Business Media LLC. - 2397-3366. ; :5, s. 510-518
-
Journal article (peer-reviewed)abstract
- Cosmic neutrinos provide a unique window into the otherwise hidden mechanism of particle acceleration in astrophysical objects. The IceCube Collaboration recently reported the likely association of one high-energy neutrino with a flare from the relativistic jet of an active galaxy pointed towards the Earth. However a combined analysis of many similar active galaxies revealed no excess from the broader population, leaving the vast majority of the cosmic neutrino flux unexplained. Here we present the likely association of a radio-emitting tidal disruption event, AT2019dsg, with a second high-energy neutrino. AT2019dsg was identified as part of our systematic search for optical counterparts to high-energy neutrinos with the Zwicky Transient Facility. The probability of finding any coincident radio-emitting tidal disruption event by chance is 0.5%, while the probability of finding one as bright in bolometric energy flux as AT2019dsg is 0.2%. Our electromagnetic observations can be explained through a multizone model, with radio analysis revealing a central engine, embedded in a UV photosphere, that powers an extended synchrotron-emitting outflow. This provides an ideal site for petaelectronvolt neutrino production. Assuming that the association is genuine, our observations suggest that tidal disruption events with mildly relativistic outflows contribute to the cosmic neutrino flux. The tidal disruption event AT2019dsg is probably associated with a high-energy neutrino, suggesting that such events can contribute to the cosmic neutrino flux. The electromagnetic emission is explained in terms of a central engine, a photosphere and an extended synchrotron-emitting outflow.
|
|
| 45. |
- Stern, Anna, 1980, et al.
(author)
-
Neonatal Mucosal Immune Stimulation by Microbial Superantigen Improves the Tolerogenic Capacity of CD103(+) Dendritic Cells
- 2013
-
In: Plos One. - : Public Library of Science (PLoS). - 1932-6203. ; 8:9
-
Journal article (peer-reviewed)abstract
- Food allergy represents failure to develop tolerance to dietary proteins. Food allergy has increased in prevalence in parallel with decreased exposure to microbes during infancy. In mice, neonatal peroral exposure to the strongly T cell stimulating superantigen staphylococcal enterotoxin A (SEA), enhances the capacity to develop oral tolerance to a novel antigen encountered in adult life. A population of antigen-presenting cells in the gut, the CD103(+) dendritic cells (DCs), is thought to be involved in oral tolerance development, as they convert naive T cells into FoxP3(+) regulatory T cells (Treg). This function depends on their capacity to convert vitamin A to retinoic acid, carried out by the retinal aldehyde dehydrogenase (RALDH) enzyme. Here, newborn mice were treated with superantigen and DC function and tolerogenic capacity was examined at six weeks of age. We observed that, in mice fed superantigen neonatally, the CD11c(+) DCs had increased expression of RALDH and in vitro more efficiently induced expression Foxp3 expression to stimulated T cells. Further, these mice showed an accumulation of FoxP3(+) T cells in the small intestinal lamina propria and had a more Ag-specific FoxP3(+) T cells after oral tolerance induction in vivo. Moreover, the improved oral tolerance, as shown by increased protection from food allergy, was eradicated if the Vitamin A metabolism was inhibited. These observations contribute to the understanding of how a strong immune stimulation during the neonatal period influences the maturation of the immune system and suggests that such stimulation may reduce the risk of later allergy development.
|
|
| 46. |
- Stern, Anna, 1980
(author)
-
The immunomodulatory function of staphylococcal superantigen on oral tolerance
- 2010
-
Doctoral thesis (other academic/artistic)abstract
- Exposure to soluble proteins via the gut gives rise to systemic tolerance, a phenomenon called oral tolerance. Failure of oral tolerance results in allergy, a disease that has increased during the last decades in Western industrialized countries. The cause of this rapid increase is unknown. However, according to the hygiene hypothesis and many epidemiological studies, there is a clear correlation between a hygienic lifestyle and the prevalence of allergy. The hygiene hypothesis is also supported by the results of animal studies. Specifically, germ-free mice have been found to be deficient in the development of oral tolerance and have less functional regulatory T cells. We have observed that Swedish infants have a less diverse gut microbial flora and a slower strain turnover compared to infants in developing countries, suggesting that certain microbes may have particularly strong immunoregulatory potential. Thus, neonatal colonization by Staphylococcus aureus (S. aureus) in the gut protects against food allergy development. Most S. aureus strains can produce one or more toxins with superantigenic function, including staphylococcal enterotoxins (SE) A, B, C, D, and E, as well as toxic shock syndrome toxin-1 (TSST-1). Superantigens are the strongest known T cell stimulants, as they stimulate 5-30% of all T cells in an antigen-independent manner by cross-linking MHC class II molecules on antigen-presenting cells with the Vβ region of the T cell receptor. The purpose of this thesis was to study the immunomodulatory role of staphylococcal superantigen on oral tolerance in animal models of allergy. Newborn pups were exposed to SEA during the first two weeks of life. Oral tolerance was induced at 6 weeks of age by feeding the mice the model antigen ovalbumin (OVA). Oral tolerization was followed by sensitization and challenge according to an airway allergy model or a food allergy model. Neonatal SEA treatment resulted in enhanced development of oral tolerance, as evidenced by decreased sensitization in both allergy models. Further, when colonizing germ-free mice with superantigen-producing S. aureus, improved oral tolerance induction in the food allergy model was observed compared to mice colonized by a non toxin-producing strain. To investigate the long-term effect of SEA on the immune system, immune cells were studied at the time for oral tolerization. We found that mice neonatally treated with SEA had higher proportions of lymphocytes expressing the gut migratory markers chemokine receptor CCR9 and integrin α4β7. This was associated with higher numbers of FoxP3+ regulatory T cells in the small intestinal lamina propria. In addition, neonatal SEA treatment rendered dendritic cells (DCs) more tolerogenic demonstrated by lower expression of co-stimulatory markers, higher expression of MHC class II, and reduced T cell stimulatory properties. A subpopulation of gut DCs expressing CD103 have been suggested to be important for oral tolerance. This DC subset specifically imprints gut migratory potential on stimulated T cells and can convert naïve T cells into regulatory T cells. The unique properties of the CD103+ DCs depend on their expression of retinal dehydrogenases (RALDHs), enzymes that convert vitamin A to retinoic acid (RA). By interfering with the vitamin A metabolism in vivo by giving mice the RALDH inhibitor Citral in their drinking water, the improvement in oral tolerance noted after neonatal SEA treatment was lost. In addition, Citral intake affected gut DCs by lowering the expression of MHC class II, suggesting that high expression of antigens via MHC class II is important for oral tolerance. In conclusion, neonatal exposure to superantigen or colonization of germ-free mice by superantigen-producing S. aureus confers an increased ability for oral tolerance several weeks after treatment. This improvement is likely dependent upon an interaction between gut-residing DCs and gut-migrating lymphocytes, particularly regulatory T cells. SEA treatment affects gut DCs inducing prolonged capacity in this subset to evoke gut-homing potential to T cells. In addition, the improved oral tolerance observed following neonatal SEA treatment might also be dependent on functional vitamin A metabolism.
|
|
| 47. |
- Stern, Jennifer C., et al.
(author)
-
Evidence for indigenous nitrogen in sedimentary and aeolian deposits from the Curiosity rover investigations at Gale crater, Mars
- 2015
-
In: Proceedings of the National Academy of Sciences of the United States of America. - : Proceedings of the National Academy of Sciences. - 0027-8424 .- 1091-6490. ; 112:14, s. 4245-4250
-
Journal article (peer-reviewed)abstract
- The Sample Analysis at Mars (SAM) investigation on the Mars Science Laboratory (MSL) Curiosity rover has detected oxidized nitrogen-bearing compounds during pyrolysis of scooped aeolian sediments and drilled sedimentary deposits within Gale crater. Total N concentrations ranged from 20 to 250 nmol N per sample. After subtraction of known N sources in SAM, our results support the equivalent of 110–300 ppm of nitrate in the Rocknest (RN) aeolian samples, and 70–260 and 330–1,100 ppm nitrate in John Klein (JK) and Cumberland (CB) mudstone deposits, respectively. Discovery of indigenous martian nitrogen in Mars surface materials has important implications for habitability and, specifically, for the potential evolution of a nitrogen cycle at some point in martian history. The detection of nitrate in both wind-drifted fines (RN) and in mudstone (JK, CB) is likely a result of N2 fixation to nitrate generated by thermal shock from impact or volcanic plume lightning on ancient Mars. Fixed nitrogen could have facilitated the development of a primitive nitrogen cycle on the surface of ancient Mars, potentially providing a biochemically accessible source of nitrogen.
|
|
| 48. |
- Stern, Jenny, et al.
(author)
-
Is pregnancy planning associated with background characteristics and pregnancy-planning behavior?
- 2016
-
In: Acta Obstetricia et Gynecologica Scandinavica. - : John Wiley & Sons. - 0001-6349 .- 1600-0412. ; 95:2, s. 182-189
-
Journal article (peer-reviewed)abstract
- Introduction Prevalence of planned pregnancies varies between countries but is often measured in a dichotomous manner. The aim of this study was to investigate to what level pregnant women had planned their pregnancies and whether pregnancy planning was associated with background characteristics and pregnancy-planning behavior. Material and methodsA cross-sectional study that utilized the baseline measurements from the Swedish Pregnancy Planning study. Pregnant women (n = 3390) recruited at antenatal clinics answered a questionnaire. Data were analyzed with multinomial logistic regression, Kruskal-Wallis H and chi-squared tests ResultsThree of four pregnancies were very or fairly planned and 12% fairly or very unplanned. Of women with very unplanned pregnancies, 32% had considered an induced abortion. Women with planned pregnancies were more likely to have a higher level of education, higher household income, to be currently working (50%) and to have longer relationships than women with unplanned pregnancies. The level of pregnancy planning was associated with planning behavior, such as information-seeking and intake of folic acid, but without a reduction in alcohol consumption. One-third of all women took folic acid 1 month prior to conception, 17% used tobacco daily and 11% used alcohol weekly 3 months before conception ConclusionsA majority rated their pregnancy as very or fairly planned, with socio-economic factors as explanatory variables. The level of pregnancy planning should be queried routinely to enable individualized counseling, especially for women with unplanned pregnancies. Preconception recommendations need to be established and communicated to the public to increase health promoting planning behavior
|
|
| 49. |
|
|
| 50. |
- Stern, Martin, et al.
(author)
-
Influence of donor/recipient sex matching on outcome of allogeneic hematopoietic stem cell transplantation for aplastic anemia
- 2006
-
In: Transplantation. - : Ovid Technologies (Wolters Kluwer Health). - 1534-6080 .- 0041-1337. ; 82:2, s. 218-226
-
Journal article (peer-reviewed)abstract
- Background. Increased risk of transplant related mortality in male recipients of female hematopoietic stem cell grafts and in vitro reactivity of lymphocytes against H-Y encoded gene products in females with rejected male grafts have been documented. An increased rejection of male grafts in female recipients is not reported for solid organ or stem cell transplants and the role of H-Y as transplantation antigen has been controversial. Methods. Data from 1481 patients with a hematopoietic stem cell transplant for aplastic anemia reported from 154 centers in 28 countries were analyzed. Outcome was compared between patients with donors of the same or opposite Sex. Results. Survival at 5 years was significantly better in patients with donors from the same sex: 68% vs. 60% (P=0.001). Male patients with female donors had a decreased survival (relative risk of death 1.52, P < 0.001) and an increased risk of severe graft-versus-host disease (relative risk 1.33, P=0.03) compared to recipients of sex-matched grafts. Female patients with male donors had a decreased survival (relative risk of death 1.44, P=0.01) and an increased risk of rejection (relative risk 2.20, P=0.01) compared to recipients of sex-matched grafts. In a subgroup analysis, the negative effects of donor/recipient sex-mismatching appeared confined to patients receiving conditioning regimens not containing antithymocyte globulin. Conclusions. These data confirm H-Y as a clinically relevant transplantation antigen, in both the graft-versus-host and the host-versus-graft direction. Wherever possible, donor-recipient sex-matching should be integrated into donor selection algorithms.
|
|
