| 1. |
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| 2. |
- Teumer, A., et al.
(författare)
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Genomewide meta-analysis identifies loci associated with IGF-I and IGFBP-3 levels with impact on age-related traits
- 2016
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Ingår i: Aging Cell. - : Wiley. - 1474-9718 .- 1474-9726. ; 15:5, s. 811-824
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Tidskriftsartikel (refereegranskat)abstract
- The growth hormone/insulin-like growth factor (IGF) axis can be manipulated in animal models to promote longevity, and IGF-related proteins including IGF-I and IGF-binding protein-3 (IGFBP-3) have also been implicated in risk of human diseases including cardiovascular diseases, diabetes, and cancer. Through genomewide association study of up to 30884 adults of European ancestry from 21 studies, we confirmed and extended the list of previously identified loci associated with circulating IGF-I and IGFBP-3 concentrations (IGF1, IGFBP3, GCKR, TNS3, GHSR, FOXO3, ASXL2, NUBP2/IGFALS, SORCS2, and CELSR2). Significant sex interactions, which were characterized by different genotype–phenotype associations between men and women, were found only for associations of IGFBP-3 concentrations with SNPs at the loci IGFBP3 and SORCS2. Analyses of SNPs, gene expression, and protein levels suggested that interplay between IGFBP3 and genes within the NUBP2 locus (IGFALS and HAGH) may affect circulating IGF-I and IGFBP-3 concentrations. The IGF-I-decreasing allele of SNP rs934073, which is an eQTL of ASXL2, was associated with lower adiposity and higher likelihood of survival beyond 90years. The known longevity-associated variant rs2153960 (FOXO3) was observed to be a genomewide significant SNP for IGF-I concentrations. Bioinformatics analysis suggested enrichment of putative regulatory elements among these IGF-I- and IGFBP-3-associated loci, particularly of rs646776 at CELSR2. In conclusion, this study identified several loci associated with circulating IGF-I and IGFBP-3 concentrations and provides clues to the potential role of the IGF axis in mediating effects of known (FOXO3) and novel (ASXL2) longevity-associated loci. © 2016 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.
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| 3. |
- Kilpeläinen, Tuomas O, et al.
(författare)
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Genome-wide meta-analysis uncovers novel loci influencing circulating leptin levels
- 2016
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 7
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Tidskriftsartikel (refereegranskat)abstract
- Leptin is an adipocyte-secreted hormone, the circulating levels of which correlate closely with overall adiposity. Although rare mutations in the leptin (LEP) gene are well known to cause leptin deficiency and severe obesity, no common loci regulating circulating leptin levels have been uncovered. Therefore, we performed a genome-wide association study (GWAS) of circulating leptin levels from 32,161 individuals and followed up loci reaching P<10(-6) in 19,979 additional individuals. We identify five loci robustly associated (P<5 × 10(-8)) with leptin levels in/near LEP, SLC32A1, GCKR, CCNL1 and FTO. Although the association of the FTO obesity locus with leptin levels is abolished by adjustment for BMI, associations of the four other loci are independent of adiposity. The GCKR locus was found associated with multiple metabolic traits in previous GWAS and the CCNL1 locus with birth weight. Knockdown experiments in mouse adipose tissue explants show convincing evidence for adipogenin, a regulator of adipocyte differentiation, as the novel causal gene in the SLC32A1 locus influencing leptin levels. Our findings provide novel insights into the regulation of leptin production by adipose tissue and open new avenues for examining the influence of variation in leptin levels on adiposity and metabolic health.
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| 4. |
- Frazier-Wood, Alexis C., et al.
(författare)
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Genetic variants associated with subjective well-being, depressive symptoms, and neuroticism identified through genome-wide analyses
- 2016
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Ingår i: Nature Genetics. - : Nature Research (part of Springer Nature). - 1061-4036 .- 1546-1718. ; 48, s. 624-
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Tidskriftsartikel (refereegranskat)abstract
- Very few genetic variants have been associated with depression and neuroticism, likely because of limitations on sample size in previous studies. Subjective well-being, a phenotype that is genetically correlated with both of these traits, has not yet been studied with genome-wide data. We conducted genome-wide association studies of three phenotypes: subjective well-being (n = 298,420), depressive symptoms (n = 161,460), and neuroticism (n = 170,911). We identify 3 variants associated with subjective well-being, 2 variants associated with depressive symptoms, and 11 variants associated with neuroticism, including 2 inversion polymorphisms. The two loci associated with depressive symptoms replicate in an independent depression sample. Joint analyses that exploit the high genetic correlations between the phenotypes (vertical bar(p) over cap vertical bar approximate to 0.8) strengthen the overall credibility of the findings and allow us to identify additional variants. Across our phenotypes, loci regulating expression in central nervous system and adrenal or pancreas tissues are strongly enriched for association.
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| 5. |
- Smith, Jennifer A, et al.
(författare)
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Genome-wide association study identifies 74 loci associated with educational attainment
- 2016
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Ingår i: Nature (London). - : Springer Science and Business Media LLC. - 1476-4687 .- 0028-0836. ; 533:7604, s. 539-542
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Tidskriftsartikel (refereegranskat)abstract
- Educational attainment is strongly influenced by social and other environmental factors, but genetic factors are estimated to account for at least 20% of the variation across individuals. Here we report the results of a genome-wide association study (GWAS) for educational attainment that extends our earlier discovery sample of 101,069 individuals to 293,723 individuals, and a replication study in an independent sample of 111,349 individuals from the UK Biobank. We identify 74 genome-wide significant loci associated with the number of years of schooling completed. Single-nucleotide polymorphisms associated with educational attainment are disproportionately found in genomic regions regulating gene expression in the fetal brain. Candidate genes are preferentially expressed in neural tissue, especially during the prenatal period, and enriched for biological pathways involved in neural development. Our findings demonstrate that, even for a behavioural phenotype that is mostly environmentally determined, a well-powered GWAS identifies replicable associated genetic variants that suggest biologically relevant pathways. Because educational attainment is measured in large numbers of individuals, it will continue to be useful as a proxy phenotype in efforts to characterize the genetic influences of related phenotypes, including cognition and neuropsychiatric diseases.
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| 6. |
- Uhlén, Mathias, et al.
(författare)
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The human secretome
- 2019
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Ingår i: Science Signaling. - : American Association for the Advancement of Science (AAAS). - 1945-0877 .- 1937-9145. ; 12:609
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Tidskriftsartikel (refereegranskat)abstract
- The proteins secreted by human cells (collectively referred to as the secretome) are important not only for the basic understanding of human biology but also for the identification of potential targets for future diagnostics and therapies. Here, we present a comprehensive analysis of proteins predicted to be secreted in human cells, which provides information about their final localization in the human body, including the proteins actively secreted to peripheral blood. The analysis suggests that a large number of the proteins of the secretome are not secreted out of the cell, but instead are retained intracellularly, whereas another large group of proteins were identified that are predicted to be retained locally at the tissue of expression and not secreted into the blood. Proteins detected in the human blood by mass spectrometry-based proteomics and antibody-based immuno-assays are also presented with estimates of their concentrations in the blood. The results are presented in an updated version 19 of the Human Protein Atlas in which each gene encoding a secretome protein is annotated to provide an open-access knowledge resource of the human secretome, including body-wide expression data, spatial localization data down to the single-cell and subcellular levels, and data about the presence of proteins that are detectable in the blood.
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| 7. |
- Augustsson, Anna, et al.
(författare)
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Challenges in assessing the health risks of consuming vegetables in metal-contaminated environments
- 2018
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Ingår i: Environment International. - : Elsevier BV. - 0160-4120 .- 1873-6750. ; 113, s. 269-280
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Tidskriftsartikel (refereegranskat)abstract
- A great deal of research has been devoted to the characterization of metal exposure due to the consumption of vegetables from urban or industrialized areas. It may seem comforting that concentrations in crops, as well as estimated exposure levels, are often found to be below permissible limits. However, we show that even a moderate increase in metal accumulation in crops may result in a significant increase in exposure. We also highlight the importance of assessing exposure levels in relation to a regional baseline. We have analyzed metal (Pb, Cd, As) concentrations in nearly 700 samples from 23 different vegetables, fruits, berries and mushrooms, collected near 21 highly contaminated industrial sites and from reference sites. Metal concentrations generally complied with permissible levels in commercial food and only Pb showed overall higher concentrations around the contaminated sites. Nevertheless, probabilistic exposure assessments revealed that the exposure to all three metals was significantly higher in the population residing around the contaminated sites, for both low-, medianand high consumers. The exposure was about twice as high for Pb and Cd, and four to six times as high for As. Since vegetable consumption alone did not result in exposure above tolerable intakes, it would have been easy to conclude that there is no risk associated with consuming vegetables grown near the contaminated sites. However, when the increase in exposure is quantified, its potential significance is harder to dismiss - especially when considering that exposure via other routes may be elevated in a similar way.
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| 8. |
- Buggert, Marcus, et al.
(författare)
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Limited immune surveillance in lymphoid tissue by cytolytic CD4+ T cells during health and HIV disease
- 2018
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Ingår i: PLoS Pathogens. - : Public Library of Science (PLoS). - 1553-7374. ; 14:4
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Tidskriftsartikel (refereegranskat)abstract
- CD4+ T cells subsets have a wide range of important helper and regulatory functions in the immune system. Several studies have specifically suggested that circulating effector CD4+ T cells may play a direct role in control of HIV replication through cytolytic activity or autocrine β-chemokine production. However, it remains unclear whether effector CD4+ T cells expressing cytolytic molecules and β-chemokines are present within lymph nodes (LNs), a major site of HIV replication. Here, we report that expression of β-chemokines and cytolytic molecules are enriched within a CD4+ T cell population with high levels of the T-box transcription factors T-bet and eomesodermin (Eomes). This effector population is predominately found in peripheral blood and is limited in LNs regardless of HIV infection or treatment status. As a result, CD4+ T cells generally lack effector functions in LNs, including cytolytic capacity and IFNγ and β-chemokine expression, even in HIV elite controllers and during acute/early HIV infection. While we do find the presence of degranulating CD4+ T cells in LNs, these cells do not bear functional or transcriptional effector T cell properties and are inherently poor to form stable immunological synapses compared to their peripheral blood counterparts. We demonstrate that CD4+ T cell cytolytic function, phenotype, and programming in the peripheral blood is dissociated from those characteristics found in lymphoid tissues. Together, these data challenge our current models based on blood and suggest spatially and temporally dissociated mechanisms of viral control in lymphoid tissues.
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| 9. |
- Erriah, M., et al.
(författare)
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Galectin-3 enhances monocyte-derived macrophage efferocytosis of apoptotic granulocytes in asthma
- 2019
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Ingår i: Respiratory Research. - : Springer Science and Business Media LLC. - 1465-993X. ; 20
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Tidskriftsartikel (refereegranskat)abstract
- BackgroundGalectin-3 is a 32kDa protein secreted by macrophages involved in processes such as cell activation, chemotaxis and phagocytosis. Galectin-3 has previously been shown to improve the ability of airway macrophages to ingest apoptotic cells (efferocytosis) in chronic obstructive pulmonary disease (COPD) and may be of interest in non-eosinophilic asthma (NEA) which is also characterised by impaired efferocytosis. It was hypothesised that the addition of exogenous galectin-3 to monocyte-derived macrophages (MDMs) derived from donors with NEA would enhance their ability to engulf apoptotic granulocytes.MethodsEligible non-smoking adults with asthma (n=19), including 7 with NEA and healthy controls (n=10) underwent a clinical assessment, venepuncture and sputum induction. MDMs were co-cultured with apoptotic granulocytes isolated from healthy donors with or without exogenous recombinant galectin-3 (50g/mL) and efferocytosis was assessed by flow cytometry. Galectin-3 expression and localisation in MDMs was visualised by immunofluorescence staining and fluorescence microscopy. Galectin-3, interleukin (IL)-6 and CXCL8 secretion were measured in cell culture supernatants by ELISA and cytometric bead array.ResultsBaseline efferocytosis (mean (standard deviation)) was lower in participants with asthma (33.2 (+/- 17.7)%) compared with healthy controls (45.3 (+/- 15.9)%; p=0.081). Efferocytosis did not differ between the participants with eosinophilic asthma (EA) (31.4 (+/- 19.2)%) and NEA (28.7 (+/- 21.5)%; p=0.748). Addition of galectin-3 significantly improved efferocytosis in asthma, particularly in NEA (37.8 (+/- 18.1)%) compared with baseline (30.4 (+/- 19.7)%; p=0.012). Efferocytosis was not associated with any of the clinical outcomes but was negatively correlated with sputum macrophage numbers (Spearman r=-0.671; p=0.017). Galectin-3 was diffusely distributed in most MDMs but formed punctate structures in 5% of MDMs. MDM galectin-3 secretion was lower in asthma (9.99 (2.67, 15.48) ng/mL) compared with the healthy controls (20.72 (11.28, 27.89) ng/mL; p=0.044) while IL-6 and CXCL8 levels were similar.Conclusions p id=Par4 Galectin-3 modulates macrophage function in asthma, indicating a potential role for galectin-3 to reverse impaired efferocytosis in NEA.
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| 10. |
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| 11. |
- Wilhelmson, Anna S K, et al.
(författare)
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Testosterone is an endogenous regulator of BAFF and splenic B cell number
- 2018
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 9:1
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Tidskriftsartikel (refereegranskat)abstract
- Testosterone deficiency in men is associated with increased risk for autoimmunity and increased B cell numbers through unknown mechanisms. Here we show that testosterone regulates the cytokine BAFF, an essential survival factor for B cells. Male mice lacking the androgen receptor have increased splenic B cell numbers, serum BAFF levels and splenic Baff mRNA. Testosterone deficiency by castration causes expansion of BAFF-producing fibro-blastic reticular cells (FRCs) in spleen, which may be coupled to lower splenic noradrenaline levels in castrated males, as an alpha-adrenergic agonist decreases splenic FRC number in vitro. Antibody-mediated blockade of the BAFF receptor or treatment with the neurotoxin 6-hydroxydopamine revert the increased splenic B cell numbers induced by castration. Among healthy men, serum BAFF levels are higher in men with low testosterone. Our study uncovers a previously unrecognized regulation of BAFF by testosterone and raises important questions about BAFF in testosterone-mediated protection against autoimmunity.
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| 12. |
- Banerjee, Indradumna, et al.
(författare)
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Slipdisc : A versatile sample preparation platform for point of care diagnostics
- 2017
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Ingår i: RSC Advances. - : Royal Society of Chemistry. - 2046-2069. ; 7:56, s. 35048-35054
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Tidskriftsartikel (refereegranskat)abstract
- We report a microfluidic sample preparation platform called "Slipdisc" based on slipchip technology. Slipdisc is a rotational slipchip that uses a unique hand-wound clockwork mechanism for precise movement of specially fabricated polycarbonate discs. In operation, the microchannels and microchambers carved on the closely aligned microfluidic discs convert from continuous filled paths to defined compartments using the slip movement. The clockwork mechanism introduced here is characterised by a food dye experiment and a conventional HRP TMB reaction before measuring lactate dehydrogenase (LDH) enzyme levels, which is a crucial biomarker for neonatal diagnostics. The colorimetry based detection of LDH was performed with an unmodified camera and an image analysis procedure based on normalising images and observing changes in red channel intensity. The analysis showed a close to unity coefficient of determination (R2 = 0.96) in detecting the LDH concentration when compared with a standard Chemical Analyser, demonstrating the excellent performance of the slipdisc platform with colorimetric detection. The versatile point of care sample preparation platform should ideally be suited for a multitude of applications at resource-limited settings.
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| 13. |
- Buhr, Katarina, et al.
(författare)
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End users’ challenges, needs and requirements for assessing resilience
- 2018
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Rapport (övrigt vetenskapligt/konstnärligt)abstract
- This report summarizes the results from the work in Task 1.3 of the SmartResilience project. Within the Work Package “Establishing the project baseline and the common framework”, Task 1.3 contributes to a better understanding of the indicators for resilience assessment by examining the actual needs from the ones responsible for such an assessment.This deliverable establishes, at an early stage in the project, a baseline for understanding end users’ current and projected challenges, needs and requirements for assessing resilience of critical infrastructures and using resilience indicators (RIs) for doing so. This is a necessary step to ensure that the resilience assessment methodology and smart RIs will be designed in ways that are useful and therefore adopted, thus delivering increased resilience for critical infrastructures, beyond the project.The identification of end users’ challenges, needs and requirements in assessing resilience within Task 1.3 has been guided by an actor analysis approach and is predominantly based on qualitative methods, consisting of semi-structured individual or group interviews with key end users connected to critical infrastructures, desktop studies and literature reviews. The task has covered eight critical infrastructures in the SmartResilience case studies (ALPHA-HOTEL) as well as an additional case study covering interconnected critical infrastructures (DSB). Furthermore, in order to take into account end users beyond these nine case studies, a literature review has been carried out as well as a survey among the Members of the Community of Users of Safe, Secure and Resilient Societies (CoU).The key findings from Task 1.3 are summarized below:Designing useful indicators requires extensive end user involvement in order to be able to integrate the indicators into existing organizational processes. There is a need to define the “work” that the indicators are supposed to do and make sure they meet the challenges of interconnected infrastructures.End users in the case studies confirmed and provided further insight into the following key challenges, which are illustrated by examples: the concept of resilience; external threats (climate change, cyber-attacks, terrorist attacks, flooding); the complexity of critical infrastructures; and data management.End users in the case studies expressed specific needs and requirements, which has been analyzed in terms of five dimensions of resilience and illustrated by examples: system/physical; information/data; organizational/business: societal/political and cognitive/decision-making.The survey to the CoU indicated that some actors do not see a need to develop RIs because they think current practices are sufficient. Although the low response rate calls for caution in interpreting the results, the responses suggests a number of challenges for the SmartResilience project. First, the need for the project to create assessments and RIs that are clearly regarded as providing added value in relation to end users’ current and projected needs. Second, the challenge to design assessments and RIs that can be widely disseminated, while at the same time taking different contexts into account.Three implications for indicator development are suggested. Firstly, indicators should be developed with an appropriate end user in mind. This means posing questions such as: What organization, and what function or user group, will use it? What is their interest in using indicators? What is their legitimacy to spread the indicator in the critical infrastructure? Secondly, indicators should be developed in dialogue with end users, in order to increase the likelihood that they cover areas that are relevant and currently not sufficiently covered; are relevant, understandable and legitimate; and are designed according to end users’ own motives for assessing resilience and perceptions of usefulness. Thirdly, indicators should be developed in alignment with end users’ organizational processes. This suggests that the project should develop indicators which are easy to understand in order to decrease the dependency of individual expertise and misunderstandings across different organizations; meet the level of capacity of resources that the organization(s) are willing to spend on assessments of resilience; and allow end users to collect, process and share (big) data, taking data security into account.
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| 14. |
- Büker, P, et al.
(författare)
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New flux based doseeresponse relationships for ozone for European forest tree species
- 2015
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Ingår i: Environmental Pollution. - : Elsevier BV. - 0269-7491. ; 206, s. 163-174
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Tidskriftsartikel (refereegranskat)abstract
- To derive O3 doseeresponse relationships (DRR) for five European forest trees species and broadleaf deciduous and needleleaf tree plant functional types (PFTs), phytotoxic O3 doses (PODy) were related to biomass reductions. PODy was calculated using a stomatal flux model with a range of cut-off thresholds (y) indicative of varying detoxification capacities. Linear regression analysis showed that DRR for PFT and individual tree species differed in their robustness. A simplified parameterisation of the flux model was tested and showed that for most non-Mediterranean tree species, this simplified model led to similarly robust DRR as compared to a species- and climate region-specific parameterisation. Experimentally induced soil water stress was not found to substantially reduce PODy, mainly due to the short duration of soil water stress periods. This study validates the stomatal O3 flux concept and represents a step forward in predicting O3 damage to forests in a spatially and temporally varying climate.
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| 15. |
- Bächle, Susanna M., et al.
(författare)
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Elevated levels of iNKT cell and NK cell activation correlate with disease progression in HIV-1 and HIV-2 infections
- 2016
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Ingår i: AIDS. - 0269-9370. ; 30:11, s. 1713-1722
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE:: In this study we aimed to investigate the frequency and activation of invariant natural killer T (iNKT) cells and natural killer (NK) cells among HIV-1, HIV-2, or dually HIV-1/HIV-2 (HIV-D)-infected individuals, in relation to markers of disease progression. DESIGN:: Whole blood samples were collected from treatment-naïve HIV-1 (n?=?23), HIV-2 (n?=?34) and HIV-D (n?=?11) infected individuals, as well as HIV-seronegative controls (n?=?25), belonging to an occupational cohort in Guinea-Bissau. METHODS:: Frequencies and activation levels of iNKT and NK cell subsets were analysed using multi-colour flow cytometry and results were related to HIV-status, CD4+ T cell levels, viral load, and T cell activation. RESULTS:: HIV-1, HIV-D, and viremic HIV-2 individuals had lower numbers of CD4+ iNKT cells in circulation compared to seronegative controls. Numbers of CD56 NK cells were also reduced in HIV-infected individuals as compared to control subjects. Notably, iNKT cell and NK cell activation levels, assessed by CD38 expression, were increased in HIV-1 and HIV-2 single, as well as dual, infections. HIV-2 viremia was associated with elevated activation levels in CD4+ iNKT cells, CD56 and CD56 NK cells, as compared to aviremic HIV-2 infection. Additionally, disease markers such as CD4+ T cell percentages, viral load, and CD4+ T cell activation were associated with CD38 expression levels of both iNKT and NK cells, which activation levels also correlated with each other. CONCLUSIONS:: Our data indicate that elevated levels of iNKT cell and NK cell activation are associated with viremia and disease progression markers in both HIV-1 and HIV-2 infections.
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| 16. |
- Fowler, Scott, et al.
(författare)
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Analytical evaluation of extended DRX with additional active cycles for light traffic
- 2015
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Ingår i: The International Journal of Computer Networks (COMNET), Elsevier. - : Elsevier. - 1389-1286. ; 77, s. 90-102
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Tidskriftsartikel (refereegranskat)abstract
- Abstract LTE and LTE-Advanced mobile technologies have integrated discontinuous reception (DRX) power saving method to optimize the power consumption at the user equipment (UE). The DRX method was proposed by the 3rd Generation Partnership Project (3GPP), and since then, the traffic behavior has been analyzed in several studies with a standard 3-state DRX model to describe the trade-off between power saving and delay. In this paper, we presented a novel 4-state and 5-state 3GPP LTE DRX mechanisms. The proposed mechanisms were developed by augmenting (an) active state(s) to deep and/or light sleep cycle of standard 3-state DRX for handling a small burst of packets, thereby bypassing the process of returning to the timer-dependent active mode. We have generated analytical models using a semi-Markov process for bursty packet data traffic and evaluated these augmented DRX mechanisms against a standard 3-state DRX method. Overall, the analytical results from varying timing parameters showed that our augmented DRX (both 4-state and 5-state) improved power saving factor (ranging between 1% and 8%) and reduced delay (ranging between 20% and 60%) compared to the standard 3-state DRX. Furthermore, the magnitude of improvement for both delay and power-saving was somewhat greater in 5-state than 4-state.
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| 17. |
- Gundlegård, David, 1978-
(författare)
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Transport Analytics Based on Cellular Network Signalling Data
- 2018
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Cellular networks of today generate a massive amount of signalling data. A large part of this signalling is generated to handle the mobility of subscribers and contains location information that can be used to fundamentally change our understanding of mobility patterns. However, the location data available from standard interfaces in cellular networks is very sparse and an important research question is how this data can be processed in order to efficiently use it for traffic state estimation and traffic planning.In this thesis, the potentials and limitations of using this signalling data in the context of estimating the road network traffic state and understanding mobility patterns is analyzed. The thesis describes in detail the location data that is available from signalling messages in GSM, GPRS and UMTS networks, both when terminals are in idle mode and when engaged in a telephone call or a data session. The potential is evaluated empirically using signalling data and measurements generated by standard cellular phones. The data used for analysis of location estimation and route classification accuracy (Paper I-IV in the thesis) is collected using dedicated hardware and software for cellular network analysis as well as tailor-made Android applications. For evaluation of more advanced methods for travel time estimation, data from GPS devices located in Taxis is used in combination with data from fixed radar sensors observing point speed and flow on the road network (Paper V). To evaluate the potential in using cellular network signalling data for analysis of mobility patterns and transport planning, real data provided by a cellular network operator is used (Paper VI).The signalling data available in all three types of networks is useful to estimate several types of traffic data that can be used for traffic state estimation as well as traffic planning. However, the resolution in time and space largely depends on which type of data that is extracted from the network, which type of network that is used and how it is processed.The thesis proposes new methods based on integrated filtering and classification as well as data assimilation and fusion that allows measurement reports from the cellular network to be used for efficient route classification and estimation of travel times. The thesis also shows that participatory sensing based on GPS equipped smartphones is useful in estimating radio maps for fingerprint-based positioning as well as estimating mobility models for use in filtering of course trajectory data from cellular networks.For travel time estimation, it is shown that the CEP-67 location accuracy based on the proposed methods can be improved from 111 meters to 38 meters compared to standard fingerprinting methods. For route classification, it is shown that the problem can be solved efficiently for highway environments using basic classification methods. For urban environments the link precision and recall is improved from 0.5 and 0.7 for standard fingerprinting to 0.83 and 0.92 for the proposed method based on particle filtering with integrity monitoring and Hidden Markov Models.Furthermore, a processing pipeline for data driven network assignment is proposed for billing data to be used when inferring mobility patterns used for traffic planning in terms of OD matrices, route choice and coarse travel times. The results of the large-scale data set highlight the importance of the underlying processing pipeline for this type of analysis. However, they also show very good potential in using large data sets for identifying needs of infrastructure investment by filtering out relevant data over large time periods.
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| 18. |
- Jaako, Pekka, et al.
(författare)
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Disruption of the 5S RNP-Mdm2 interaction significantly improves the erythroid defect in a mouse model for Diamond-Blackfan anemia.
- 2015
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Ingår i: Leukemia. - : Springer Science and Business Media LLC. - 1476-5551 .- 0887-6924. ; 29:11, s. 2221-2229
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Tidskriftsartikel (refereegranskat)abstract
- Diamond-Blackfan anemia (DBA) is a congenital erythroid hypoplasia caused by haploinsufficiency of genes encoding ribosomal proteins (RPs). Perturbed ribosome biogenesis in DBA has been shown to induce a p53-mediated ribosomal stress response. However, the mechanisms of p53 activation and its relevance for the erythroid defect remain elusive. Previous studies have indicated that activation of p53 is caused by the inhibition of Mdm2, the main negative regulator of p53, by the 5S ribonucleoprotein particle (RNP). Meanwhile, it is not clear whether this mechanism solely mediates the p53-dependent component found in DBA. To approach this question, we crossed our mouse model for RPS19-deficient DBA with Mdm2(C305F) knock-in mice that have a disrupted 5S RNP-Mdm2 interaction. Upon induction of the Rps19 deficiency, Mdm2(C305F) reversed the p53 response and improved expansion of hematopoietic progenitors in vitro, and ameliorated the anemia in vivo. Unexpectedly, disruption of the 5S RNP-Mdm2 interaction also led to selective defect in erythropoiesis. Our findings highlight the sensitivity of erythroid progenitor cells to aberrations in p53 homeostasis mediated by the 5S RNP-Mdm2 interaction. Finally, we provide evidence indicating that physiological activation of the 5S RNP-Mdm2-p53 pathway may contribute to functional decline of the hematopoietic system in a cell-autonomous manner over time.Leukemia accepted article preview online, 19 May 2015. doi:10.1038/leu.2015.128.
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| 19. |
- Koymans, Kirsten J, et al.
(författare)
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The TLR2 Antagonist Staphylococcal Superantigen-Like Protein 3 Acts as a Virulence Factor to Promote Bacterial Pathogenicity in vivo
- 2017
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Ingår i: Journal of Innate Immunity. - : S. Karger AG. - 1662-811X .- 1662-8128. ; 9, s. 561-573
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Tidskriftsartikel (refereegranskat)abstract
- Toll-like receptor (TLR) signaling is important in the initiation of immune responses and subsequent instigation of adaptive immunity. TLR2 recognizes bacterial lipoproteins and plays a central role in the host defense against bacterial infections, including those caused by Staphylococcus aureus. Many studies have demonstrated the importance of TLR2 in murine S. aureus infection. S. aureus evades TLR2 activation by secreting two proteins, staphylococcal superantigen-like protein 3 (SSL3) and 4 (SSL4). In this study, we demonstrate that antibodies against SSL3 and SSL4 are found in healthy individuals, indicating that humans are exposed to these proteins during S. aureus colonization or infection. To investigate the TLR2-antagonistic properties of SSL3 and SSL4, we compared the infection with wild-type and SSL3/4 knockout S. aureus strains in an intravenous murine infection model. Direct evaluation of the contribution of SSL3/4 to infection pathogenesis was hindered by the fact that the SSLs were not expressed in the murine system. To circumvent this limitation, an SSL3-overproducing strain (pLukM-SSL3) was generated, resulting in constitutive expression of SSL3. pLukM-SSL3 exhibited increased virulence compared to the parental strain in a murine model that was found to be TLR2 dependent. Altogether, these data indicate that SSL3 contributes to S. aureus virulence in vivo.
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| 20. |
- Lengyel, Tamas, 1986, et al.
(författare)
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Pre-emphasis enabled 50 Gbit/s transmission over 1000 m SMF using a 1060 nm single-mode VCSEL
- 2018
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Ingår i: Electronics Letters. - : Institution of Engineering and Technology (IET). - 1350-911X .- 0013-5194. ; 54:20, s. 1186-1187
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Tidskriftsartikel (refereegranskat)abstract
- A single-mode 1060 nm vertical-cavity surface-emitting laser (VCSEL) and single-mode fibre (SMF) based link with two-tap active pre-emphasis enabling error-free transmission of 50 Gbit/s NRZ-OOK over 1000 m is presented.
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| 21. |
- Lind, Leili, 1954-, et al.
(författare)
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COPD patients require more health care than heart failure patients
- 2018
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Ingår i: ERS International Congress 2018.
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Konferensbidrag (refereegranskat)abstract
- Background: Populations of elderly patients with advanced stages of chronic obstructive pulmonary disease (COPD) or heart failure (HF) are growing, urging the need for specialized health care in the patients’ home. A 4 year (2013-2017) telehealth intervention single-centre clinical study has been completed. We hypothesized that the two groups of patients, advanced COPD or HF, would exhibit differences regarding exacerbations and the need of health care.Objective: To study exacerbations of COPD or HF, and patients’ need of health care.Methods: A telemonitoring system, the Health Diary, which is based on digital pen technology, was employed. Patients with at least 2 hospital admissions the previous year were included. Responsible nurses and physicians at a specialized home care unit at a university hospital checked all daily patient reports. Physicians identified exacerbations using information provided through the telemonitoring system and patient contacts. Consumed health care was assessed as the number of patient contacts (home visits or telephone consultations).Results: Totally, 94 patients with advanced disease were enrolled (36 COPD and 58 HF patients) of which 53 patients (19 COPD and 34 HF patients) completed the 1-yr study period. The major reason for not completing the study was death (13 COPD, 15 HF patients). Average numbers of exacerbations were 3.1 and 0.8 and patient contacts were 94 and 67 per COPD and HF patient, respectively.Conclusions: Compared to HF patients, COPD patients exhibit exacerbations more frequently and demand much more home health care. This difference of health care consumption is mainly due to disease characteristics.
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| 22. |
- Morrill, Johan, et al.
(författare)
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β-Mannanase-catalyzed synthesis of alkyl mannooligosides
- 2018
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Ingår i: Applied Microbiology and Biotechnology. - : Springer Science and Business Media LLC. - 0175-7598 .- 1432-0614. ; 102:12, s. 5149-5163
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Tidskriftsartikel (refereegranskat)abstract
- β-Mannanases catalyze the conversion and modification of β-mannans and may, in addition to hydrolysis, also be capable of transglycosylation which can result in enzymatic synthesis of novel glycoconjugates. Using alcohols as glycosyl acceptors (alcoholysis), β-mannanases can potentially be used to synthesize alkyl glycosides, biodegradable surfactants, from renewable β-mannans. In this paper, we investigate the synthesis of alkyl mannooligosides using glycoside hydrolase family 5 β-mannanases from the fungi Trichoderma reesei (TrMan5A and TrMan5A-R171K) and Aspergillus nidulans (AnMan5C). To evaluate β-mannanase alcoholysis capacity, a novel mass spectrometry-based method was developed that allows for relative comparison of the formation of alcoholysis products using different enzymes or reaction conditions. Differences in alcoholysis capacity and potential secondary hydrolysis of alkyl mannooligosides were observed when comparing alcoholysis catalyzed by the three β-mannanases using methanol or 1-hexanol as acceptor. Among the three β-mannanases studied, TrMan5A was the most efficient in producing hexyl mannooligosides with 1-hexanol as acceptor. Hexyl mannooligosides were synthesized using TrMan5A and purified using high-performance liquid chromatography. The data suggests a high selectivity of TrMan5A for 1-hexanol as acceptor over water. The synthesized hexyl mannooligosides were structurally characterized using nuclear magnetic resonance, with results in agreement with their predicted β-conformation. The surfactant properties of the synthesized hexyl mannooligosides were evaluated using tensiometry, showing that they have similar micelle-forming properties as commercially available hexyl glucosides. The present paper demonstrates the possibility of using β-mannanases for alkyl glycoside synthesis and increases the potential utilization of renewable β-mannans.
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| 23. |
- Olbjern, Christine, et al.
(författare)
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Fecal microbiota profiles in treatment-naive pediatric inflammatory bowel disease : associations with disease phenotype, treatment, and outcome
- 2019
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Ingår i: Clinical and Experimental Gastroenterology. - Macclesfield, United Kingdom : DOVE MEDICAL PRESS LTD. - 1178-7023. ; 12, s. 37-49
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: Imbalance in the microbiota, dysbiosis, has been identified in inflammatory bowel disease (IBD). We explored the fecal microbiota in pediatric patients with treatment-naive IBD, non-IBD patients with gastrointestinal symptoms and healthy children, its relation to IBD subgroups, and treatment outcomes. Patients and methods: Fecal samples were collected from 235 children below 18 years of age. Eighty children had Crohns disease (CD), 27 ulcerative colitis (UC), 3 IBD unclassified, 50 were non-IBD symptomatic patients, and 75 were healthy. The bacterial abundance of 54 predefined DNA markers was measured with a 16S rRNA DNA-based test using GA-Map (TM) technology at diagnosis and after therapy in IBD patients. Results: Bacterial abundance was similarly reduced in IBD and non-IBD patients in 51 of 54 markers compared to healthy patients (Pamp;lt;0.001). Only Prevotella was more abundant in patients (Pamp;lt;0.01). IBD patients with ileocolitis or total colitis had more Ruminococcus gnavus (P=0.02) than patients with colonic CD or left-sided UC. CD patients with upper gastrointestinal manifestations had higher Veillonella abundance (Pamp;lt;0.01). IBD patients (58%) who received biologic therapy had lower baseline Firmicutes and Mycoplasma hominis abundance (Pamp;lt;0.01) than conventionally treated. High Proteobacteria abundance was associated with stricturing/penetrating CD, surgery (Pamp;lt;0.01), and nonmucosal healing (Pamp;lt;0.03). Low Faecalibacterium prausnitzii abundance was associated with prior antibiotic therapy (P=0.001), surgery (P=0.02), and nonmucosal healing (Pamp;lt;0.03). After therapy, IBD patients had unchanged dysbiosis. Conclusion: Fecal microbiota profiles differentiated IBD and non-IBD symptomatic children from healthy children, but displayed similar dysbiosis in IBD and non-IBD symptomatic patients. Pretreatment fecal microbiota profiles may be of prognostic value and aid in treatment individualization in pediatric IBD as severe dysbiosis was associated with an extensive, complicated phenotype, biologic therapy, and nonmucosal healing. The dysbiosis persisted after therapy, regardless of treatments and mucosal healing.
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| 24. |
- Raphel, J., et al.
(författare)
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Engineered protein coatings to improve the osseointegration of dental and orthopaedic implants
- 2016
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Ingår i: Biomaterials. - : Elsevier BV. - 0142-9612 .- 1878-5905. ; 83, s. 269-282
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Tidskriftsartikel (refereegranskat)abstract
- Here we present the design of an engineered, elastin-like protein (ELP) that is chemically modified to enable stable coatings on the surfaces of titanium-based dental and orthopaedic implants by novel photocrosslinking and solution processing steps. The ELP includes an extended RGD sequence to confer bio-signaling and an elastin-like sequence for mechanical stability. ELP thin films were fabricated on cpTi and Ti6A14V surfaces using scalable spin and dip coating processes with photoactive covalent cross linking through a carbene insertion mechanism. The coatings withstood procedures mimicking dental screw and hip replacement stem implantations, a key metric for clinical translation. They promoted rapid adhesion of MG63 osteoblast-like cells, with over 80% adhesion after 24 h, compared to 38% adhesion on uncoated Ti6A14V. MG63 cells produced significantly more mineralization on ELP coatings compared to uncoated Ti6A14V. Human bone marrow mesenchymal stem cells (hMSCs) had an earlier increase in alkaline phosphatase activity, indicating more rapid osteogenic differentiation and mineral deposition on adhesive ELP coatings. Rat tibia and femur in vivo studies demonstrated that cell -adhesive ELP-coated implants increased bone-implant contact area and interfacial strength after one week. These results suggest that ELP coatings withstand surgical implantation and promote rapid osseointegration, enabling earlier implant loading and potentially preventing micromotion that leads to aseptic loosening and premature implant failure.
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| 25. |
- Reif, Raymond, et al.
(författare)
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Bile canalicular dynamics in hepatocyte sandwich cultures
- 2015
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Ingår i: Archives of Toxicology. - : Springer Science and Business Media LLC. - 1432-0738 .- 0340-5761. ; 89:10, s. 1861-1870
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Tidskriftsartikel (refereegranskat)abstract
- Many substances are hepatotoxic due to their ability to cause intrahepatic cholestasis. Therefore, there is a high demand for in vitro systems for the identification of cholestatic properties of new compounds. Primary hepatocytes cultivated in collagen sandwich cultures are known to establish bile canaliculi which enclose secreted biliary components. Cholestatic compounds are mainly known to inhibit bile excretion dynamics, but may also alter canalicular volume, or hepatocellular morphology. So far, techniques to assess time-resolved morphological changes of bile canaliculi in sandwich cultures are not available. In this study, we developed an automated system that quantifies dynamics of bile canaliculi recorded in conventional time-lapse image sequences. We validated the hepatocyte sandwich culture system as an appropriate model to study bile canaliculi in vitro by showing structural similarity measured as bile canaliculi length per hepatocyte to that observed in vivo. Moreover, bile canalicular excretion kinetics of CMFDA (5-chloromethylfluorescein diacetate) in sandwich cultures resembled closely the kinetics observed in vivo. The developed quantification technique enabled the quantification of dynamic changes in individual bile canaliculi. With this technique, we were able to clearly distinguish between sandwich cultures supplemented with dexamethasone and insulin from control cultures. In conclusion, the automated quantification system offers the possibility to systematically study the causal relationship between disturbed bile canalicular dynamics and cholestasis.
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| 26. |
- Shen, Sipeng, et al.
(författare)
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A multi-omic study reveals BTG2 as a reliable prognostic marker for early-stage non-small cell lung cancer
- 2018
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Ingår i: Molecular Oncology. - : Wiley. - 1574-7891 .- 1878-0261. ; 12:6, s. 913-924
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Tidskriftsartikel (refereegranskat)abstract
- B-cell translocation gene 2 (BTG2) is a tumour suppressor protein known to be downregulated in several types of cancer. In this study, we investigated a potential role for BTG2 in early-stage non-small cell lung cancer (NSCLC) survival. We analysed BTG2 methylation data from 1230 early-stage NSCLC patients from five international cohorts, as well as gene expression data from 3038 lung cancer cases from multiple cohorts. Three CpG probes (cg01798157, cg06373167, cg23371584) that detected BTG2 hypermethylation in tumour tissues were associated with lower overall survival. The prognostic model based on methylation could distinguish patient survival in the four cohorts [hazard ratio (HR) range, 1.51-2.21] and the independent validation set (HR = 1.85). In the expression analysis, BTG2 expression was positively correlated with survival in each cohort (HR range, 0.28-0.68), which we confirmed with meta-analysis (HR = 0.61, 95% CI 0.54-0.68). The three CpG probes were all negatively correlated with BTG2 expression. Importantly, an integrative model of BTG2 methylation, expression and clinical information showed better predictive ability in the training set and validation set. In conclusion, the methylation and integrated prognostic signatures based on BTG2 are stable and reliable biomarkers for early-stage NSCLC. They may have new applications for appropriate clinical adjuvant trials and personalized treatments in the future.
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| 27. |
- Simpanen, Ewa, 1987, et al.
(författare)
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1060 nm Single-Mode VCSEL and Single-Mode Fiber Links for Long-Reach Optical Interconnects
- 2019
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Ingår i: Journal of Lightwave Technology. - 0733-8724 .- 1558-2213. ; 37:13, s. 2963-2969
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Tidskriftsartikel (refereegranskat)abstract
- We investigate the use of a 1060 nm single-mode vertical-cavity surface-emitting laser (VCSEL) and a 1060 nm single-mode fiber as a competitive single-mode technology for cost-and power-efficient long-reach optical interconnects. Error-free transmission (bit error rate < 10-12) over 2 km is demonstrated at bitrates up to 40 Gb/s under on-off keying non-return-to-zero (OOK-NRZ) modulation, without equalization, forward-error correction, or other forms of digital signal processing. The VCSEL is extensively characterized with respect to its static and dynamic performances, including the power-voltage-current characteristics, spectral characteristics, beam divergence, modulation response, relative intensity noise, and frequency chirp. The measured dependence of power penalty on fiber length is consistent with an analysis of chirp-induced pulse compression and broadening along the negative chromatic dispersion fiber.
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| 28. |
- Sundström, Johan, Professor, 1971-, et al.
(författare)
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Rationale for a Swedish cohort consortium
- 2019
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Ingår i: Upsala Journal of Medical Sciences. - : Taylor & Francis Group. - 0300-9734 .- 2000-1967. ; 124:1, s. 21-28
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Tidskriftsartikel (refereegranskat)abstract
- We herein outline the rationale for a Swedish cohort consortium, aiming to facilitate greater use of Swedish cohorts for world-class research. Coordination of all Swedish prospective population-based cohorts in a common infrastructure would enable more precise research findings and facilitate research on rare exposures and outcomes, leading to better utilization of study participants' data, better return of funders' investments, and higher benefit to patients and populations. We motivate the proposed infrastructure partly by lessons learned from a pilot study encompassing data from 21 cohorts. We envisage a standing Swedish cohort consortium that would drive development of epidemiological research methods and strengthen the Swedish as well as international epidemiological competence, community, and competitiveness.
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| 29. |
- Vikström, Kevin, 1988-
(författare)
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Importance of bacterial maintenance respiration and baseline respiration for development of coastal hypoxia
- 2018
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Reduced oxygen concentrations and increasing hypoxic zones havebecome more common in the sea due to climate change andeutrophication. The main cause of oxygen loss in oxygenatedenvironments is respiration. Respiration rates can be estimated usingoptode methodologies which utilize dynamic luminescence quenching toestimate the oxygen concentration declines in dark incubations. Apublished optode methodology was improved by using optodes withtitanium housing instead of plastic housing plausibly trapping oxygen.Drift was highly reduced by the titanium casings leading to a higherprecision and lower detection limit of 0.97 mmol O2 m-3 d-1. 28% ofmeasurements were shown to have non-linear oxygen concentrationdeclines. The rate of oxygen change was derived with a 2nd degreepolynomial at 1 hour from the incubation start. The majority of non-lineardeclines were concave and due to carbon substrate limitation. Analyzingnon-linear trends linearly, a common practice, leads to anunderestimation of respiration by up to 64%.Bacterial maintenance respiration (Rm) was studied using anecophysiological model unverified in natural environments. The modelwas applicable at high productivities but a quadratic model wasdemonstrated to give a better fit. Rm was found to represent a significantpart in the sub-arctic estuary contributing to 58% of the annual specificbacterial respiration. Therefore, Rm may be more important in nature thanpreviously recognized. The ecophysiological model is driven solely by thebacterial specific growth rate (μ) where the relative influence of Rm iselevated as μ decreases. As a consequence, I hypothesize that a reductionin nutrients may not decrease the oxygen consumption but rather shiftbacterial growth based respiration to Rm as μ approaches zero.Baseline respiration (Rbl), defined as ecosystem respiration disconnectedfrom contemporary primary produced carbon, was also studied. Rbl wasshown to be largely supplied by allochthonous carbon in a coastalecosystem and had a contribution of 50% to the annual planktoncommunity respiration in the sub-arctic estuary studied. I claim that Rbland Rm are crucial to include for understanding and managingdevelopment of aquatic hypoxia in an effective and economic manner.
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| 30. |
- Wei, Yongyue, et al.
(författare)
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Epigenetic modifications inlysine demethylases associate with survival of early-stage NSCLC
- 2018
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Ingår i: Clinical Epigenetics. - : Springer Science and Business Media LLC. - 1868-7075 .- 1868-7083. ; 10
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Tidskriftsartikel (refereegranskat)abstract
- Background: KDMlysine demethylase family members are related to lung cancer clinical outcomes and are potential biomarkers for chemotherapeutics. However, little is known about epigenetic alterations inKDMgenes and their roles in lung cancer survival.Methods: Tumor tissue samples of 1230 early-stage non-small cell lung cancer (NSCLC) patients were collected from the five independent cohorts. The 393 methylation sites inKDMgenes were extracted from epigenome-wide datasets and analyzed by weighted random forest (Ranger) in discovery phase and validation dataset, respectively. The variable importance scores (VIS) for the sites in top 5% of both discovery and validation sets were carried forward for Cox regression to further evaluate the association with patient's overall survival. TCGA transcriptomic data were used to evaluate the correlation with the corresponding DNA methylation.Results: DNA methylation at sites cg11637544 inKDM2Aand cg26662347 inKDM1Awere in the top 5% of VIS in both discovery phase and validation for squamous cell carcinomas (SCC), which were also significantly associated with SCC survival (HRcg11637544 = 1.32, 95%CI, 1.16-1.50,P = 1.1 × 10-4;HRcg26662347 = 1.88, 95%CI, 1.37-2.60,P = 3.7 × 10-3), and correlated with corresponding gene expression (cg11637544 forKDM2A,P = 1.3 × 10-10; cg26662347 forKDM1A P = 1.5 × 10-5). In addition, by using flexible criteria for Ranger analysis followed by survival classification tree analysis, we identified four clusters for adenocarcinomas and five clusters for squamous cell carcinomas which showed a considerable difference of clinical outcomes with statistical significance.Conclusions: These findings highlight the association between somatic DNA methylation inKDMgenes and early-stage NSCLC patient survival, which may reveal potential epigenetic therapeutic targets.
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| 31. |
- Zhu, B., et al.
(författare)
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Fusion of Sensors Data in Automotive Radar Systems : A Spectral Estimation Approach
- 2019
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Ingår i: Proceedings of the IEEE Conference on Decision and Control. - : Institute of Electrical and Electronics Engineers Inc.. - 9781728113982 ; , s. 5088-5093
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Konferensbidrag (refereegranskat)abstract
- To accurately estimate locations and velocities of surrounding targets (cars) is crucial for advanced driver assistance systems based on radar sensors. In this paper we derive methods for fusing data from multiple radar sensors in order to improve the accuracy and robustness of such estimates. First we pose the target estimation problem as a multivariate multidimensional spectral estimation problem. The problem is multivariate since each radar sensor gives rise to a measurement channel. Then we investigate how the use of the cross-spectra affects target estimates. We see that the use of the magnitude of the cross-spectrum significantly improves the accuracy of the target estimates, whereas an attempt to compensate the phase lag of the cross-spectrum only gives marginal improvement. This paper may be viewed as a first step towards applying high-resolution methods that builds on multidimensional multivariate spectral estimation for sensor fusion.
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