| 1. |
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| 2. |
- Jandrić, Petar, et al.
(författare)
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Teaching in the Age of Covid-19
- 2020
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Ingår i: Postdigital Science and Education. - : Springer Science and Business Media LLC. - 2524-4868 .- 2524-485X. ; 2:3, s. 1069-1230
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- A collection of 84 author's testimonies and workspace photographs between 18 March and 5 May 2020.
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| 3. |
- Jandrić, Petar, et al.
(författare)
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Teaching in the Age of Covid-19 : The New Normal
- 2022
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Ingår i: Postdigital Science and Education. - : Springer Science and Business Media LLC. - 2524-485X .- 2524-4868. ; 4:3, s. 877-1015
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Tidskriftsartikel (refereegranskat)abstract
- On 17 March 2020, Postdigital Science and Education launched a call for testimonies about teaching and learning during very frst Covid-19 lockdowns. The resulting article, ‘Teaching in the Age of Covid-19’ (attached), presents 81 written testimonies and 80 workspace photographs submitted by 84 authors from 19 countries. On 17 March 2021, Postdigital Science and Education launched a call for a sequel article of testimonies about teaching and learning during very first Covid-19 lockdowns. The resulting article, ‘Teaching in the Age of Covid-19—1 Year Later’(attached), consists of 74 textual testimonies and 76 workspace photographs submitted by 77 authors from 20 countries.These two articles have been downloaded almost 100,000 times and have been cited more than 100 times. This shows their value as historical documents. Recent analyses, such as ‘Teaching in the Age of Covid-19—A Longitudinal Study ’(attached), also indicate their strong potential for educational research. As the Covid-19 pandemic seems to wind down, pandemic experiences have entered the mainstream. They shape all educational research of today and arguably do not require special treatment. Yet, our unique series of pandemic testimonies provides a unique opportunity to longitudinally trace what happens to the same people over the years—and this opportunity should not be missed.Today, we launch a call for fnal sequel: Teaching in the Age of Covid-19—The New Normal. In this sequel, we would like to hear about ways in which you—contributors to the previous articles—have established your own new normal. We hope that this will be the last iteration in this series of testimony articles. Unless the world faces another strong pandemic outburst, we would like to end the series with this last article.
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| 4. |
- Jandrić, Petar, et al.
(författare)
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Teaching in the Age of Covid-19—1 Year Later
- 2021
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Ingår i: Postdigital Science and Education. - : Springer. - 2524-485X .- 2524-4868. ; 3:3, s. 1073-1223
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Tidskriftsartikel (refereegranskat)
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| 5. |
- Klionsky, Daniel J., et al.
(författare)
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Guidelines for the use and interpretation of assays for monitoring autophagy
- 2012
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Ingår i: Autophagy. - : Informa UK Limited. - 1554-8635 .- 1554-8627. ; 8:4, s. 445-544
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Forskningsöversikt (refereegranskat)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.
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| 6. |
- Meier, H. E. Markus, et al.
(författare)
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Assessment of Eutrophication Abatement Scenarios for the Baltic Sea by Multi-Model Ensemble Simulations
- 2018
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Ingår i: Frontiers in Marine Science. - : Frontiers Media SA. - 2296-7745. ; 5
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Tidskriftsartikel (refereegranskat)abstract
- To assess the impact of the implementation of the Baltic Sea Action Plan (BSAP) on the future environmental status of the Baltic Sea, available uncoordinated multi-model ensemble simulations for the Baltic Sea region for the twenty-first century were analyzed. The scenario simulations were driven by regionalized global general circulation model (GCM) data using several regional climate system models and forced by various future greenhouse gas emission and air- and river-borne nutrient load scenarios following either reference conditions or the BSAP. To estimate uncertainties in projections, the largest ever multi-model ensemble for the Baltic Sea comprising 58 transient simulations for the twenty-first century was assessed. Data from already existing simulations from different projects including regionalized GCM simulations of the third and fourth assessment reports of the Intergovernmental Panel on Climate Change based on the corresponding Coupled Model Intercomparison Projects, CMIP3 and CMIP5, were collected.Various strategies to weigh the ensemble members were tested and the results for ensemble mean changes between future and present climates are shown to be robust with respect to the chosen metric. Although (1) the model simulations during the historical period are of different quality and (2) the assumptions on nutrient load levels during present and future periods differ between models considerably, the ensemble mean changes in biogeochemical variables in the Baltic proper with respect to nutrient load reductions are similar between the entire ensemble and a subset consisting only of the most reliable simulations.Despite the large spread in projections, the implementation of the BSAP will lead to a significant improvement of the environmental status of the Baltic Sea according to both weighted and unweighted ensembles. The results emphasize the need for investigating ensembles with many members and rigorous assessments of models’ performance.
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| 7. |
- Meier, H. E. Markus, et al.
(författare)
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Assessment of Uncertainties in Scenario Simulations of Biogeochemical Cycles in the Baltic Sea
- 2019
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Ingår i: Frontiers in Marine Science. - : Frontiers Media SA. - 2296-7745. ; 6
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Forskningsöversikt (refereegranskat)abstract
- Following earlier regional assessment studies, such as the Assessment of Climate Change for the Baltic Sea Basin and the North Sea Region Climate Change Assessment, knowledge acquired from available literature about future scenario simulations of biogeochemical cycles in the Baltic Sea and their uncertainties is assessed. The identification and reduction of uncertainties of scenario simulations are issues for marine management. For instance, it is important to know whether nutrient load abatement will meet its objectives of restored water quality status in future climate or whether additional measures are required. However, uncertainties are large and their sources need to be understood to draw conclusions about the effectiveness of measures. The assessment of sources of uncertainties in projections of biogeochemical cycles based on authors' own expert judgment suggests that the biggest uncertainties are caused by (1) unknown current and future bioavailable nutrient loads from land and atmosphere, (2) the experimental setup (including the spin up strategy), (3) differences between the projections of global and regional climate models, in particular, with respect to the global mean sea level rise and regional water cycle, (4) differing model-specific responses of the simulated biogeochemical cycles to long-term changes in external nutrient loads and climate of the Baltic Sea region, and (5) unknown future greenhouse gas emissions. Regular assessments of the models' skill (or quality compared to observations) for the Baltic Sea region and the spread in scenario simulations (differences among projected changes) as well as improvement of dynamical downscaling methods are recommended.
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| 8. |
- Sassi, Atfa, et al.
(författare)
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Hypomorphic homozygous mutations in phosphoglucomutase 3 (PGM3) impair immunity and increase serum IgE levels
- 2014
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Ingår i: Journal of Allergy and Clinical Immunology. - : Elsevier BV. - 0091-6749 .- 1097-6825. ; 133:5, s. 1410-U681
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Tidskriftsartikel (refereegranskat)abstract
- Background: Recurrent bacterial and fungal infections, eczema, and increased serum IgE levels characterize patients with the hyper-IgE syndrome (HIES). Known genetic causes for HIES are mutations in signal transducer and activator of transcription 3 (STAT3) and dedicator of cytokinesis 8 (DOCK8), which are involved in signal transduction pathways. However, glycosylation defects have not been described in patients with HIES. One crucial enzyme in the glycosylation pathway is phosphoglucomutase 3 (PGM3), which catalyzes a key step in the synthesis of uridine diphosphate N-acetylglucosamine, which is required for the biosynthesis of N-glycans. Objective: We sought to elucidate the genetic cause in patients with HIES who do not carry mutations in STAT3 or DOCK8. Methods: After establishing a linkage interval by means of SNPchip genotyping and homozygosity mapping in 2 families with HIES from Tunisia, mutational analysis was performed with selector-based, high-throughput sequencing. Protein expression was analyzed by means of Western blotting, and glycosylation was profiled by using mass spectrometry. Results: Mutational analysis of candidate genes in an 11.9-Mb linkage region on chromosome 6 shared by 2 multiplex families identified 2 homozygous mutations in PGM3 that segregated with disease status and followed recessive inheritance. The mutations predict amino acid changes in PGM3 (p. Glu340del and p. Leu83Ser). A third homozygous mutation (p. Asp502Tyr) and the p. Leu83Ser variant were identified in 2 other affected families, respectively. These hypomorphic mutations have an effect on the biosynthetic reactions involving uridine diphosphate N-acetylglucosamine. Glycomic analysis revealed an aberrant glycosylation pattern in leukocytes demonstrated by a reduced level of tri-antennary and tetra-antennary N-glycans. T-cell proliferation and differentiation were impaired in patients. Most patients had developmental delay, and many had psychomotor retardation. Conclusion: Impairment of PGM3 function leads to a novel primary (inborn) error of development and immunity because biallelic hypomorphic mutations are associated with impaired glycosylation and a hyper-IgE-like phenotype.
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| 9. |
- Armgarth, Astrid, et al.
(författare)
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A digital nervous system aiming toward personalized IoT healthcare
- 2021
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Ingår i: Scientific Reports. - : NATURE RESEARCH. - 2045-2322. ; 11:1
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Tidskriftsartikel (refereegranskat)abstract
- Body area networks (BANs), cloud computing, and machine learning are platforms that can potentially enable advanced healthcare outside the hospital. By applying distributed sensors and drug delivery devices on/in our body and connecting to such communication and decision-making technology, a system for remote diagnostics and therapy is achieved with additional autoregulation capabilities. Challenges with such autarchic on-body healthcare schemes relate to integrity and safety, and interfacing and transduction of electronic signals into biochemical signals, and vice versa. Here, we report a BAN, comprising flexible on-body organic bioelectronic sensors and actuators utilizing two parallel pathways for communication and decision-making. Data, recorded from strain sensors detecting body motion, are both securely transferred to the cloud for machine learning and improved decision-making, and sent through the body using a secure body-coupled communication protocol to auto-actuate delivery of neurotransmitters, all within seconds. We conclude that both highly stable and accurate sensing-from multiple sensors-are needed to enable robust decision making and limit the frequency of retraining. The holistic platform resembles the self-regulatory properties of the nervous system, i.e., the ability to sense, communicate, decide, and react accordingly, thus operating as a digital nervous system.
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| 10. |
- Badam, Tejaswi, et al.
(författare)
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CD4(+) T-cell DNA methylation changes during pregnancy significantly correlate with disease-associated methylation changes in autoimmune diseases
- 2022
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Ingår i: Epigenetics. - : Taylor & Francis Group. - 1559-2294 .- 1559-2308. ; 17:9, s. 1040-1055
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Tidskriftsartikel (refereegranskat)abstract
- Epigenetics may play a central, yet unexplored, role in the profound changes that the maternal immune system undergoes during pregnancy and could be involved in the pregnancy-induced modulation of several autoimmune diseases. We investigated changes in the methylome in isolated circulating CD4(+) T-cells in non-pregnant and pregnant women, during the 1(st) and 2(nd) trimester, using the Illumina Infinium Human Methylation 450K array, and explored how these changes were related to autoimmune diseases that are known to be affected during pregnancy. Pregnancy was associated with several hundreds of methylation differences, particularly during the 2(nd) trimester. A network-based modular approach identified several genes, e.g., CD28, FYN, VAV1 and pathways related to T-cell signalling and activation, highlighting T-cell regulation as a central component of the observed methylation alterations. The identified pregnancy module was significantly enriched for disease-associated methylation changes related to multiple sclerosis, rheumatoid arthritis and systemic lupus erythematosus. A negative correlation between pregnancy-associated methylation changes and disease-associated changes was found for multiple sclerosis and rheumatoid arthritis, diseases that are known to improve during pregnancy whereas a positive correlation was found for systemic lupus erythematosus, a disease that instead worsens during pregnancy. Thus, the directionality of the observed changes is in line with the previously observed effect of pregnancy on disease activity. Our systems medicine approach supports the importance of the methylome in immune regulation of T-cells during pregnancy. Our findings highlight the relevance of using pregnancy as a model for understanding and identifying disease-related mechanisms involved in the modulation of autoimmune diseases.
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| 11. |
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| 12. |
- Björnsson, Bergthor, et al.
(författare)
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Digital twins to personalize medicine
- 2020
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Ingår i: Genome Medicine. - : Springer Science and Business Media LLC. - 1756-994X. ; 12:1
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Forskningsöversikt (refereegranskat)abstract
- Personalized medicine requires the integration and processing of vast amounts of data. Here, we propose a solution to this challenge that is based on constructing Digital Twins. These are high-resolution models of individual patients that are computationally treated with thousands of drugs to find the drug that is optimal for the patient.
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| 13. |
- Broadaway, K Alaine, et al.
(författare)
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Loci for insulin processing and secretion provide insight into type 2 diabetes risk.
- 2023
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Ingår i: American Journal of Human Genetics. - : Elsevier. - 0002-9297 .- 1537-6605. ; 110:2, s. 284-299
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Tidskriftsartikel (refereegranskat)abstract
- Insulin secretion is critical for glucose homeostasis, and increased levels of the precursor proinsulin relative to insulin indicate pancreatic islet beta-cell stress and insufficient insulin secretory capacity in the setting of insulin resistance. We conducted meta-analyses of genome-wide association results for fasting proinsulin from 16 European-ancestry studies in 45,861 individuals. We found 36 independent signals at 30 loci (p value < 5 × 10-8), which validated 12 previously reported loci for proinsulin and ten additional loci previously identified for another glycemic trait. Half of the alleles associated with higher proinsulin showed higher rather than lower effects on glucose levels, corresponding to different mechanisms. Proinsulin loci included genes that affect prohormone convertases, beta-cell dysfunction, vesicle trafficking, beta-cell transcriptional regulation, and lysosomes/autophagy processes. We colocalized 11 proinsulin signals with islet expression quantitative trait locus (eQTL) data, suggesting candidate genes, including ARSG, WIPI1, SLC7A14, and SIX3. The NKX6-3/ANK1 proinsulin signal colocalized with a T2D signal and an adipose ANK1 eQTL signal but not the islet NKX6-3 eQTL. Signals were enriched for islet enhancers, and we showed a plausible islet regulatory mechanism for the lead signal in the MADD locus. These results show how detailed genetic studies of an intermediate phenotype can elucidate mechanisms that may predispose one to disease.
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| 14. |
- Brunnström, Pål, et al.
(författare)
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Samverkan inom forskning : Malmö universitets arbete för att understödja, följa upp och utveckla forskningssamverkan
- 2017
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Rapport (övrigt vetenskapligt/konstnärligt)abstract
- Syftet med undersökningen är att ta fram ett förslag på en satsning för att understödja, följa upp och utveckla Malmö högskolas forskningssamverkan. Forskningsläget visar att det finns stora skillnader i hur samverkan bedrivs vid olika institutioner och olika lärosäten. Utifrån det övergripande syftet genomförs därför två olika undersökningar: Dels undersöks de samverkansaktiviteter som Malmö högskola och forskare vid högskolan är inblandade i idag, genom intervjuer med forskare, ledning och externa samverkanspartner. Dels undersöks exempel på framgångsrik forskningssamverkan som bedrivs vid andra lärosäten, via studiebesök på dessa och intervjuer med centrala personer. Undersökningen resulterar i ett antal förslag på åtgärder, inom följande områden: Kommunikation, Organisatorisk förändring och stödåtgärder, Resurser och incitament, Ledning, reglering och styrdokument, Kunskapsutveckling samt Kompetensutveckling och utbildning. Projektet har finanseriets av Vinnova.
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| 15. |
- Di Rocco, Sandra, et al.
(författare)
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Conditional Euclidean distance optimization via relative tangency
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- We introduce a theory of relative tangency for projective algebraic varieties. The dual variety X∨Z of a variety X relative to a subvariety Z is the set of hyperplanes tangent to X at a point of Z. We also introduce the concept of polar classes of X relative to Z. We explore the duality of varieties of low rank matrices relative to special linear sections. In this framework, we study the critical points of the Euclidean Distance function from a data point to X, lying on Z. The locus where the number of such conditional critical points is positive is called the ED data locus of X given Z. The generic number of such critical points defines the conditional ED degree of X given Z.We show the irreducibility of ED data loci, and we compute their dimensions and degrees in terms of relative characteristic classes
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| 16. |
- Di Rocco, Sandra, et al.
(författare)
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Gaussian likelihood geometry of projective varieties
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- We explore the maximum likelihood degree of a homogeneous polynomial F on a projective variety X, MLD_F(X), which generalizes the concept of Gaussian maximum likelihood degree. We show that MLD_F(X) is equal to the count of critical points of a rational function on X, and give different geometric characterizations of it via topological Euler characteristic, dual varieties, and Chern classes.
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| 17. |
- Di Rocco, Sandra, et al.
(författare)
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Gaussian Likelihood Geometry of Projective Varieties
- 2024
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Ingår i: SIAM Journal on Applied Algebra and Geometry. - : Society for Industrial and Applied Mathematics Publications. - 2470-6566. ; 8:1, s. 89-113
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Tidskriftsartikel (refereegranskat)abstract
- We explore the maximum likelihood degree of a homogeneous polynomial F on a projective variety X, MLDF(X), which generalizes the concept of Gaussian maximum likelihood degree. We show that MLDF(X) is equal to the count of critical points of a rational function on X and give different geometric characterizations of it via topological Euler characteristic, dual varieties, and Chern classes.
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| 18. |
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| 19. |
- El-Serafi, Ahmed, 1977-, et al.
(författare)
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Vitamin D levels and busulphan kinetics in patients undergoing hematopoietic stem cell transplantation, a multicenter study
- 2021
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Ingår i: Bone Marrow Transplantation. - : SPRINGERNATURE. - 0268-3369 .- 1476-5365. ; 56, s. 807-817
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Tidskriftsartikel (refereegranskat)abstract
- Vitamin D (Vit-D), an essential nutrient, interacts with different drugs including chemotherapeutic agents like busulphan, an alkylating agent used for conditioning prior to stem cell transplantation. The correlation between Vit-D plasma levels and busulphan clearance was investigated in an uncontrolled prospective study in patients and mice. Plasma 25(OH)D levels were measured and busulphan pharmacokinetics calculated in 81 patients. Adults received oral busulphan (n = 34) while children received busulphan orally (n = 19) or intravenously (n = 28). Patients received no Vit-D supplementation. To confirm our findings, pharmacokinetics after a single dose of busulphan (oral or intravenous) were evaluated in two groups of mice (n = 60) receiving high or standard-level Vit-D supplementation. Both busulphan clearance (P < 0.0001) and 25(OH)D levels (P = 0.0004) were significantly higher in adults compared to children. A significant negative correlation (P = 0.041) was found between busulphan clearance and 25(OH)D levels in children treated orally. No such correlation was observed in adults or in children receiving intravenous busulphan. In addition, no significant effect of Vit-D levels on busulphan pharmacokinetics in mice regardless of the administration route. In conclusion, 25(OH)D can affect oral busulphan pharmacokinetics in children and its level should be considered when personalizing oral busulphan treatment. Further studies are warranted to confirm the underlying mechanisms.
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| 20. |
- Fakhro, Mohammed, et al.
(författare)
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25-year follow-up after lung transplantation at Lund University Hospital in Sweden : superior results obtained for patients with cystic fibrosis
- 2016
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Ingår i: Interactive Cardiovascular and Thoracic Surgery. - : Oxford University Press (OUP). - 1569-9285 .- 1569-9293. ; 23:1, s. 65-73
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVES: In Sweden, two centres perform lung transplantation for a population of about 9 million and the entire population is covered for lung transplantation by government health insurance. Lund University Hospital is one of these centres. This retrospective report reviews the 25-year experience of the Skåne University Hospital Lung Transplant Program with particular emphasis on short-term outcome and long-term survival but also between different subgroups of patients and types of transplant [single-lung transplantation (SLTx) versus double-lung transplantation (DLTx)] procedure performed.METHODS: Between January 1990 and June 2014, 278 patients underwent lung transplantation at the Skåne University Hospital Sweden. DLTx was performed in 172 patients, SLTx was performed in 97 patients and heart-lung transplantation was performed in 9 patients. In addition, 15 patients required retransplantation (7 DLTx and 8 SLTx).RESULTS: Overall 1-, 5-, 10-, 15- and 20-year survival rates were 88, 65, 49, 37 and 19% for the whole cohort. DLTx recipients showed 1-, 5-, 10- and 20-year survival rates of 90, 71, 60 and 30%, compared with SLTx recipients with 1-, 5-, 10- and 20-year survival rates of 83, 57, 34 and 6% (P < 0.05), respectively. Comparing the use of intraoperative extracorporeal membrane oxygenation, extracorporeal circulation (ECC) and no circulatory support in the aspect of survival, a significant difference in favour of intraoperative ECC was seen.CONCLUSIONS: Superior long-term survival rates were seen in recipients diagnosed with cystic fibrosis, α1-antitrypsin deficiency and pulmonary hypertension. DLTx showed better results compared with SLTx especially at 10 years post-transplant. In the present study, we present cumulative incidence rates of bronchiolitis obliterans syndrome of 15% at 5 years, 26% at 10 years and 32% at 20 years post-transplant; these figures are in line with the lowest rates presented internationally.
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| 21. |
- Fakhro, Mohammed, et al.
(författare)
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Double lung, unlike single lung transplantation might provide a protective effect on mortality and bronchiolitis obliterans syndrome
- 2017
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Ingår i: Journal of Cardiothoracic Surgery. - : Springer Science and Business Media LLC. - 1749-8090. ; 12:1
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Survival after lung transplantation (LTx) is often limited by bronchiolitis obliterans syndrome (BOS).METHOD: Survey of 278 recipients who underwent LTx. The endpoint used was BOS (BOS grade ≥ 2), death or Re-lung transplantation (Re-LTx) assessed by competing risk regression analyses.RESULTS: The incidence of BOS grade ≥ 2 among double LTx (DLTx) recipients was 16 ± 3% at 5 years, 30 ± 4% at 10 years, and 37 ± 5% at 20 years, compared to single LTx (SLTx) recipients whose corresponding incidence of BOS grade ≥ 2 was 11 ± 3%, 20 ± 4%, and 24 ± 5% at 5, 10, and 20 years, respectively (p > 0. 05). The incidence of BOS grade ≥ 2 by major indications ranked in descending order: other, PF, CF, COPD, PH and AAT1 (p < 0. 05). The mortality rate by major indication ranked in descending order: COPD, PH, AAT1, PF, Other and CF (p < 0. 05).CONCLUSION: No differences were seen in the incidence of BOS grade ≥ 2 regarding type of transplant, however, DLTx recipients showed a better chance of survival despite developing BOS compared to SLTx recipients. The highest incidence of BOS was seen among CF, PF, COPD, PH, and AAT1 recipients in descending order, however, CF and PF recipients showed a better chance of survival despite developing BOS compared to COPD, PH, and AAT1 recipients.
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| 22. |
- Gawel, Danuta, et al.
(författare)
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A validated single-cell-based strategy to identify diagnostic and therapeutic targets in complex diseases
- 2019
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Ingår i: Genome Medicine. - : Springer Science and Business Media LLC. - 1756-994X. ; 11
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Tidskriftsartikel (refereegranskat)abstract
- Background: Genomic medicine has paved the way for identifying biomarkers and therapeutically actionable targets for complex diseases, but is complicated by the involvement of thousands of variably expressed genes across multiple cell types. Single-cell RNA-sequencing study (scRNA-seq) allows the characterization of such complex changes in whole organs. Methods: The study is based on applying network tools to organize and analyze scRNA-seq data from a mouse model of arthritis and human rheumatoid arthritis, in order to find diagnostic biomarkers and therapeutic targets. Diagnostic validation studies were performed using expression profiling data and potential protein biomarkers from prospective clinical studies of 13 diseases. A candidate drug was examined by a treatment study of a mouse model of arthritis, using phenotypic, immunohistochemical, and cellular analyses as read-outs. Results: We performed the first systematic analysis of pathways, potential biomarkers, and drug targets in scRNA-seq data from a complex disease, starting with inflamed joints and lymph nodes from a mouse model of arthritis. We found the involvement of hundreds of pathways, biomarkers, and drug targets that differed greatly between cell types. Analyses of scRNA-seq and GWAS data from human rheumatoid arthritis (RA) supported a similar dispersion of pathogenic mechanisms in different cell types. Thus, systems-level approaches to prioritize biomarkers and drugs are needed. Here, we present a prioritization strategy that is based on constructing network models of disease-associated cell types and interactions using scRNA-seq data from our mouse model of arthritis, as well as human RA, which we term multicellular disease models (MCDMs). We find that the network centrality of MCDM cell types correlates with the enrichment of genes harboring genetic variants associated with RA and thus could potentially be used to prioritize cell types and genes for diagnostics and therapeutics. We validated this hypothesis in a large-scale study of patients with 13 different autoimmune, allergic, infectious, malignant, endocrine, metabolic, and cardiovascular diseases, as well as a therapeutic study of the mouse arthritis model. Conclusions: Overall, our results support that our strategy has the potential to help prioritize diagnostic and therapeutic targets in human disease.
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| 23. |
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| 24. |
- Gustafsson, Karin, 1980, et al.
(författare)
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Tumour-loaded alpha-type 1-polarized Dendritic Cells from Patients with Chronic Lymphocytic Leukaemia Produce a Superior NK-, NKT- and CD8(+) T Cell-attracting Chemokine Profile
- 2011
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Ingår i: Scandinavian Journal of Immunology. - 0300-9475. ; 74:3, s. 318-326
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Tidskriftsartikel (refereegranskat)abstract
- Tumour-loaded dendritic cells (DCs) from patients with chronic lymphocytic leukaemia (CLL) matured using an α-type 1-polarized DC cocktail (IL-1β/TNF-α/IFN-α/IFN-γ/poly-I:C;αDC1) were recently shown to induce more functional CD8+ T cells against autologous tumour cells in vitro than DCs matured with the ‘standard’ cocktail (IL-1β/TNF-α/IL-6/PGE2;PGE2DCs). However, the ability of vaccine DCs to induce a type 1-polarized immune response in vivo probably relies on additional features, including their ability to induce a CXCR3-dependent recruitment of NK cells into vaccine-draining lymph nodes. Moreover, their guiding of rare tumour-specific CD8+ T cells to sites of DC–CD4+ T cell interactions by secretion of CCL3 and CCL4 is needed. We therefore analysed the chemokine profile and the lymphocyte-attracting ability in vitro of monocyte-derived PGE2DCs and αDC1s from patients with CLL. αDC1s produced much higher levels of CXCR3 ligands (CXCL9/CXCL10/CXCL11) than PGE2DCs. Functional studies further demonstrated that αDC1s were superior recruiters of both NK and NKT cells. Moreover, αDC1s produced higher levels of CCL3/CCL4 upon CD40 ligation. These findings suggest that functional αDC1s, derived from patients with CLL, produce a desirable NK-, NKT- and CD8+ T cell-attracting chemokine profile which may favour a guided and Th1-deviated priming of CD8+ T cells, supporting the idea that αDC1-based vaccines have a higher immunotherapeutic potential than PGE2DCs.
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| 25. |
- Gustafsson, Karin, et al.
(författare)
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Tumour-loaded alpha-type 1-polarized Dendritic Cells from Patients with Chronic Lymphocytic Leukaemia Produce a Superior NK-, NKT- and CD8(+) T Cell-attracting Chemokine Profile
- 2011
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Ingår i: Scandinavian Journal of Immunology. - : Wiley. - 0300-9475 .- 1365-3083. ; 74:3, s. 318-326
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Tidskriftsartikel (refereegranskat)abstract
- Tumour-loaded dendritic cells (DCs) from patients with chronic lymphocytic leukaemia (CLL) matured using an a-type 1-polarized DC cocktail (IL-1 beta/TNF-alpha/IFN-alpha/IFN-gamma/poly-I:C;alpha DC1) were recently shown to induce more functional CD8(+) T cells against autologous tumour cells in vitro than DCs matured with the 'standard' cocktail (IL-1 beta/TNF-alpha/IL-6/PGE(2);PGE(2)DCs). However, the ability of vaccine DCs to induce a type 1-polarized immune response in vivo probably relies on additional features, including their ability to induce a CXCR3-dependent recruitment of NK cells into vaccine-draining lymph nodes. Moreover, their guiding of rare tumour-specific CD8(+) T cells to sites of DC-CD4(+) T cell interactions by secretion of CCL3 and CCL4 is needed. We therefore analysed the chemokine profile and the lymphocyte-attracting ability in vitro of monocyte-derived PGE(2)DCs and alpha DC1s from patients with CLL. alpha DC1s produced much higher levels of CXCR3 ligands (CXCL9/CXCL10/CXCL11) than PGE(2)DCs. Functional studies further demonstrated that alpha DC1s were superior recruiters of both NK and NKT cells. Moreover, alpha DC1s produced higher levels of CCL3/CCL4 upon CD40 ligation. These findings suggest that functional alpha DC1s, derived from patients with CLL, produce a desirable NK-, NKT- and CD8(+) T cell-attracting chemokine profile which may favour a guided and Th1-deviated priming of CD8(+) T cells, supporting the idea that alpha DC1-based vaccines have a higher immunotherapeutic potential than PGE(2)DCs.
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| 26. |
- Gustafsson, Lukas
(författare)
-
Topics in projective algebraic optimization
- 2023
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- This thesis explores optimization challenges within algebraic statistics, employing both topological and geometrical methodologies to derive new insights. The main focus is the optimization degree of nearest point and Gaussian maximum likelihood estimation problems with algebraic constraints. The optimization degree counts the number of complex critical points for an optimization problem. It is interesting as it can aid numerical solvers by providing an upper bound on the number of solutions to a set of equations, without computing them explicitly. The study extends to a parallel research trajectory, complementing and expanding the primary themes by studying relative tangency for critical point loci and characterizing the ideal of the line-multiview variety, inspiring further study of reconstructing 3D objects from 2D images in computer vision. Paper A focuses on linear concentration models and critical point counts for the Gaussian log-likelihood function when restricted to a linear space. The paper unveils new Gaussian maximum likelihood degree formulae from line geometry and Segre classes. We also study codimension one models and scenarios with zero maximum likelihood degree in particular.In Paper B, we extend the inquiry from Paper A by exploring Gaussian likelihood geometry of arbitrary projective varieties. We introduce the maximum likelihood degree of a homogeneous polynomial on a projective variety, delving into quantifying critical points for a rational function. We find geometric characterizations of the maximum likelihood degree in terms of Euler characteristics, dual varieties, and Chern classes.Paper C advances the investigation into multivariate Gaussian statistical models with rational maximum likelihood estimator (MLE). A correspondence is established between such models and solutions to a nonlinear first-order partial differential equation (PDE). This link sheds light on the problem of classifying Gaussian models with rational MLE, relating it to the open problem of classification of homaloidal polynomials in birational geometry.Paper D computes the generic, or expected, maximum likelihood degree of a variety as an analog to the known polar class formula for the Euclidean distance degree. Additionally, as a follow-up to paper C, the complex projective curves of maximum likelihood degree 1 are classified in paper D. This allows further work into when a complex curve can be realized as a real statistical models. Both paper C and D connect the maximum likelihood degree as a possible generalization to the Euclidean distance degree for projective varieties.Paper E intersects algebraic geometry and computer vision, focusing on projected lines from multiple pinhole cameras. The line multiview variety captures these projections as an algebraic variety. The main result establishes the ideal of this variety, generated by 3x3-minors of a matrix derived from projected line equations. The predecessor of the line-multiview variety is the point-multiview variety, with image correction being a driving motivation for introducing the Euclidean distance degree. Notably, Paper E opens the door for studying the Euclidean distance degree of the line-multiview variety and its uses in 3D reconstruction.Paper F delves into the concept of Euclidean distance estimates within the context of a specific subset of the available data. To contruct a robust foundational theory, this paper introduces the concepts of relative duality and relative characteristic classes. It demonstrates that classical formulas can be equivalently expressed in the relative setting, thereby shedding light on the geometric intricacies inherent to this relative analysis.
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| 27. |
- Gustafsson, Mika, et al.
(författare)
-
A validated gene regulatory network and GWAS identifies early regulators of T cell-associated diseases
- 2015
-
Ingår i: Science Translational Medicine. - : AMER ASSOC ADVANCEMENT SCIENCE. - 1946-6234 .- 1946-6242. ; 7:313
-
Tidskriftsartikel (refereegranskat)abstract
- Early regulators of disease may increase understanding of disease mechanisms and serve as markers for presymptomatic diagnosis and treatment. However, early regulators are difficult to identify because patients generally present after they are symptomatic. We hypothesized that early regulators of T cell-associated diseases could be found by identifying upstream transcription factors (TFs) in T cell differentiation and by prioritizing hub TFs that were enriched for disease-associated polymorphisms. A gene regulatory network (GRN) was constructed by time series profiling of the transcriptomes and methylomes of human CD4(+) T cells during in vitro differentiation into four helper T cell lineages, in combination with sequence-based TF binding predictions. The TFs GATA3, MAF, and MYB were identified as early regulators and validated by ChIP-seq (chromatin immunoprecipitation sequencing) and small interfering RNA knockdowns. Differential mRNA expression of the TFs and their targets in T cell-associated diseases supports their clinical relevance. To directly test if the TFs were altered early in disease, T cells from patients with two T cell-mediated diseases, multiple sclerosis and seasonal allergic rhinitis, were analyzed. Strikingly, the TFs were differentially expressed during asymptomatic stages of both diseases, whereas their targets showed altered expression during symptomatic stages. This analytical strategy to identify early regulators of disease by combining GRNs with genome-wide association studies may be generally applicable for functional and clinical studies of early disease development.
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| 28. |
- Gustafsson, Sandra, et al.
(författare)
-
Amyloid Fibril Composition as a Predictor of Development of Cardiomyopathy After Liver Transplantation for Hereditary Transthyretin Amyloidosis
- 2012
-
Ingår i: Transplantation. - 0041-1337 .- 1534-6080. ; 93:10, s. 1017-1023
-
Tidskriftsartikel (refereegranskat)abstract
- Background. Liver transplantation (LTx) is an accepted treatment for hereditary transthyretin (TTR) amyloidosis (ATTR). However, unforeseen heart complications, especially a rapid development of cardiomyopathy after LTx has affected mortality and morbidity. Recently, a relationship between ATTR-fibril composition and cardiomyopathy has been noted. The aim of this study was to investigate whether development of cardiomyopathy and heart failure in LTx ATTR amyloid patients is related to amyloid fibril composition.Methods. Twenty-four patients with hereditary ATTR amyloidosis who had undergone LTx and have had their amyloid fibril type tested were available for the study. They had been examined by echocardiography including tissue Doppler and speckle tracking echocardiography before and after LTx. Patients were divided into two groups according to fibril composition, 10 patients with type A fibrils (a mixture of truncated and full-length TTR) and 14 patients with type B fibrils (full-length TTR fibrils only). There was no difference in time to the follow-up echocardiography between the two groups.Results. After LTx, the group consisting of type A patients developed symptoms of heart failure and with reduced systolic and diastolic ventricular function as shown by echocardiography, whereas no similar deterioration was noted for the group of patients with type B fibrils.Conclusion. Patients with type A fibrils deteriorate an already existing cardiomyopathy and heart failure after LTx, in contrast to patients with type B fibrils. These results might have significant clinical implications in optimizing best patients selection criteria for LTx.
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| 29. |
- Gustafsson, Sandra, et al.
(författare)
-
Can echocardiography differentiate hereditary transthyretin amyloidosis from hypertrophic cardiomyopathy?
- 2013
-
Ingår i: European Heart Journal. - : Oxford University Press. - 0195-668X .- 1522-9645. ; 34:Supplement: 1, s. 213-213
-
Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- Purpose: Hereditary transthyretin amyloidosis (ATTR) andhypertrophic cardiomyopathy (HCM) have many phenotypic similarities when examined by echocardiography. As the two conditions have different treatment strategies it is of importance to accurately diagnose these patients early in the disease. This study aimed to identify the most accurate echocardiographic method in differentiating these two conditions by using traditional and speckle tracking echocardiographyas well as myocardial texture analysis.Methods: We investigated 40 healthy controls, 33 patients with biopsy proven ATTR and 20 with HCM. All patients had septal thickness >12 mm. We measured left ventricular (LV) global strain as intrinsic systolic function and LV E/e' to estimate filling pressures. We also tested septal cyclic integrated backscatter (cIBS) and septal entropy as both being measures for myocardial highly reflection pattern whereas cIBS showing motion of highly reflective echoes and entropy the distribution of highly reflective echoes.Results: LV global strain, cIBS and E/e' were not useful in differentiating ATTR from HCM. However, septal entropy was found to be significantly different and showed an area under the curve from ROC analysis of 0.66 separating ATTR from HCM.Conclusion: After using detailed analysis of different aspects of LV morphology and function we found that myocardial texture behavior from entropy analysis was the only method useful in differentiating patients with ATTR fromHCM.
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| 30. |
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| 31. |
- Hagenbjörk-Gustafsson, Annika, et al.
(författare)
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Determinants of personal exposure to some carcinogenic substances and nitrogen dioxide among the general population in five Swedish cities
- 2014
-
Ingår i: Journal of Exposure Science and Environmental Epidemiology. - : Springer Science and Business Media LLC. - 1559-0631 .- 1559-064X. ; 24:4, s. 437-443
-
Tidskriftsartikel (refereegranskat)abstract
- Environmental levels of airborne carcinogenic and related substances are comparatively better known than individual exposure and its determinants. We report on a personal monitoring program involving five Swedish urban populations. The aim of the program was to investigate personal exposure to benzene, 1,3-butadiene, formaldehyde, and nitrogen dioxide (NO2). The measurements were performed among 40 inhabitants during seven consecutive days, in one urban area each year, during 2000-2008. The estimated population exposure levels were 1.95 mu g/m(3) for benzene, 0.56 mu g/m(3) for 1,3-butadiene, 19.4 mu g/m(3) for formaldehyde, and 14.1,mu g/m(3) for NO2. Statistical analysis using a mixed-effects model revealed that time spent in traffic and time outdoors contributed to benzene and 1,3- butadiene exposure. For benzene, refueling a car was an additional determinant influencing the exposure level. Smoking or environmental tobacco smoke were significant determinants of exposure to NO2, benzene, and 1, 3-butadiene. Those with a gas stove had higher NO2 exposure. Living in a single-family house increased the exposure to formaldehyde significantly. In a variance component model, the between-subject variance dominated for 1,3-butadiene and formaldehyde, whereas the between-city variance dominated for NO2. For benzene, the between-subject and between-cities variances were similar.
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| 32. |
- Heinonen, Essi, et al.
(författare)
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MAGDALENA : study protocol of a randomised, placebo-controlled trial on cognitive development at 2 years of age in children exposed to SSRI in utero
- 2018
-
Ingår i: BMJ Open. - : BMJ Publishing Group Ltd. - 2044-6055. ; 8:8
-
Tidskriftsartikel (refereegranskat)abstract
- Introduction Ten per cent of all pregnant women are depressed. Standard therapy of pregnant women with moderate depression is selective serotonin reuptakeinhibitors (SSRI). Observational studies on neurodevelopment after fetal SSRI exposure show conflicting results. Our primary objective is to compare the cognitive development in children exposed to sertraline and maternal depression with those exposed to maternal depression and placebo in utero. We hypothesise that there is a significant neurodevelopmental difference between the groups. As a secondary objective, we study the add-on effect of sertraline to internet-based cognitive behavioural therapy (ICBT) to treat moderate depression during pregnancy. Methods and analysis MAGDALENA is a randomised, placebo-controlled, double-blinded trial in Stockholm Healthcare Region with 2.3 million inhabitants. The women are recruited in weeks 9-21 of pregnancy either through Antenatal Health Clinics or through social media. They are to be diagnosed with moderate depression without ongoing antidepressive therapy or any serious comorbidity. The women in the intervention arm receive sertraline combined with a 12-week period of ICBT; the control arm is treated with placebo and ICBT. We assess the cognitive development in the offspring at the age of 2 years using Bayley Scales of Infant and Toddler Development, third edition (BSID-III). We aim at recruiting 200 women, 100 women in each treatment arm, to ensure statistical power to detect a clinically relevant difference between the groups. Ethics and dissemination This randomised trial will provide long-sought evidence about the effects of SSRI and maternal depression during pregnancy on the neurodevelopment in the offspring. The study is approved by the Regional Ethical Review Board at Karolinska Institutet in Stockholm and the Swedish Medical Products Agency. It is registered with the European Clinical Trials Database (EudraCT), Number: 2013-004444-31. Results will be disseminated at scientific conferences, published in peer-reviewed journals and made available to the public.
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| 33. |
- Hellberg, Sandra, et al.
(författare)
-
Dynamic Response Genes in CD4+ T Cells Reveal a Network of Interactive Proteins that Classifies Disease Activity in Multiple Sclerosis
- 2016
-
Ingår i: Cell Reports. - : Cell Press. - 2211-1247. ; 16:11, s. 2928-2939
-
Tidskriftsartikel (refereegranskat)abstract
- Multiple sclerosis (MS) is a chronic inflammatory disease of the CNS and has a varying disease course as well as variable response to treatment. Biomarkers may therefore aid personalized treatment. We tested whether in vitro activation of MS patient-derived CD4+ T cells could reveal potential biomarkers. The dynamic gene expression response to activation was dysregulated in patient-derived CD4+ T cells. By integrating our findings with genome-wide association studies, we constructed a highly connected MS gene module, disclosing cell activation and chemotaxis as central components. Changes in several module genes were associated with differences in protein levels, which were measurable in cerebrospinal fluid and were used to classify patients from control individuals. In addition, these measurements could predict disease activity after 2 years and distinguish low and high responders to treatment in two additional, independent cohorts. While further validation is needed in larger cohorts prior to clinical implementation, we have uncovered a set of potentially promising biomarkers.
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| 34. |
- Hellberg, Sandra, et al.
(författare)
-
Progesterone Dampens Immune Responses in In Vitro Activated CD4(+) T Cells and Affects Genes Associated With Autoimmune Diseases That Improve During Pregnancy
- 2021
-
Ingår i: Frontiers in Immunology. - : Frontiers Media SA. - 1664-3224. ; 12
-
Tidskriftsartikel (refereegranskat)abstract
- The changes in progesterone (P4) levels during and after pregnancy coincide with the temporary improvement and worsening of several autoimmune diseases like multiple sclerosis (MS) and rheumatoid arthritis (RA). Most likely immune-endocrine interactions play a major role in these pregnancy-induced effects. In this study, we used next generation sequencing to investigate the direct effects of P4 on CD4(+) T cell activation, key event in pregnancy and disease. We report profound dampening effects of P4 on T cell activation, altering the gene and protein expression profile and reversing many of the changes induced during the activation. The transcriptomic changes induced by P4 were significantly enriched for genes associated with diseases known to be modulated during pregnancy such as MS, RA and psoriasis. STAT1 and STAT3 were significantly downregulated by P4 and their downstream targets were significantly enriched among the disease-associated genes. Several of these genes included well-known and disease-relevant cytokines, such as IL-12 beta, CXCL10 and OSM, which were further validated also at the protein level using proximity extension assay. Our results extend the previous knowledge of P4 as an immune regulatory hormone and support its importance during pregnancy for regulating potentially detrimental immune responses towards the semi-allogenic fetus. Further, our results also point toward a potential role for P4 in the pregnancy-induced disease immunomodulation and highlight the need for further studies evaluating P4 as a future treatment option.
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| 35. |
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| 36. |
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| 37. |
- Ingemansson, Richard, et al.
(författare)
-
Clinical transplantation of initially rejected donor lungs after reconditioning ex vivo.
- 2009
-
Ingår i: Annals of Thoracic Surgery. - : Elsevier BV. - 1552-6259 .- 0003-4975. ; 87:1, s. 255-260
-
Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: A major problem in clinical lung transplantation is the shortage of donor lungs. Only about 20% of donor lungs are accepted for transplantation. A method to evaluate and recondition lungs ex vivo has been tested on donor lungs that have been rejected for transplantation. METHODS: The donor lungs were reconditioned ex vivo in an extracorporeal membrane oxygenation (ECMO) circuit with STEEN solution (Vitrolife AB, Kungsbacka, Sweden) mixed with erythrocytes. The hyperoncotic solution dehydrates edematous lung tissue. Functional evaluations were performed with deoxygenated perfusate by varying the inspired fraction of oxygen. After the reconditioning, the lungs were kept immersed at 8 degrees C in extracorporeal membrane oxygenation until transplantation was performed. RESULTS: Six of nine initially rejected donor lungs were reconditioned to acceptable function, and in six recipients, double lung transplantation was performed. Three-month survival was 100%. One patient has since died due to sepsis after 95 days, and one due to rejection after 9 months. Four recipients are alive and well without any sign of bronchiolitis obliterans syndrome 24 months after the transplantation. CONCLUSIONS: The result from the present study is promising, and we continue to transplant reconditioned lungs.
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| 38. |
- Kanoni, Stavroula, et al.
(författare)
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Implicating genes, pleiotropy, and sexual dimorphism at blood lipid loci through multi-ancestry meta-analysis.
- 2022
-
Ingår i: Genome biology. - : Springer Science and Business Media LLC. - 1474-760X .- 1465-6906 .- 1474-7596. ; 23:1
-
Tidskriftsartikel (refereegranskat)abstract
- Genetic variants within nearly 1000 loci are known to contribute to modulation of blood lipid levels. However, the biological pathways underlying these associations are frequently unknown, limiting understanding of these findings and hindering downstream translational efforts such as drug target discovery.To expand our understanding of the underlying biological pathways and mechanisms controlling blood lipid levels, we leverage a large multi-ancestry meta-analysis (N=1,654,960) of blood lipids to prioritize putative causal genes for 2286 lipid associations using six gene prediction approaches. Using phenome-wide association (PheWAS) scans, we identify relationships of genetically predicted lipid levels to other diseases and conditions. We confirm known pleiotropic associations with cardiovascular phenotypes and determine novel associations, notably with cholelithiasis risk. We perform sex-stratified GWAS meta-analysis of lipid levels and show that 3-5% of autosomal lipid-associated loci demonstrate sex-biased effects. Finally, we report 21 novel lipid loci identified on the X chromosome. Many of the sex-biased autosomal and X chromosome lipid loci show pleiotropic associations with sex hormones, emphasizing the role of hormone regulation in lipid metabolism.Taken together, our findings provide insights into the biological mechanisms through which associated variants lead to altered lipid levels and potentially cardiovascular disease risk.
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| 39. |
- Landegren, Nils, et al.
(författare)
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Transglutaminase 4 as a prostate autoantigen in male subfertility
- 2015
-
Ingår i: Science Translational Medicine. - : American Association for the Advancement of Science. - 1946-6234 .- 1946-6242. ; 7:292
-
Tidskriftsartikel (refereegranskat)abstract
- Autoimmune polyendocrine syndrome type 1 (APS1), a monogenic disorder caused by AIRE gene mutations, features multiple autoimmune disease components. Infertility is common in both males and females with APS1. Although female infertility can be explained by autoimmune ovarian failure, the mechanisms underlying male infertility have remained poorly understood. We performed a proteome-wide autoantibody screen in APS1 patient sera to assess the autoimmune response against the male reproductive organs. By screening human protein arrays with male and female patient sera and by selecting for gender-imbalanced autoantibody signals, we identified transglutaminase 4 (TGM4) as a male-specific autoantigen. Notably, TGM4 is a prostatic secretory molecule with critical role in male reproduction. TGM4 autoantibodies were detected in most of the adult male APS1 patients but were absent in all the young males. Consecutive serum samples further revealed that TGM4 autoantibodies first presented during pubertal age and subsequent to prostate maturation. We assessed the animal model for APS1, the Aire-deficient mouse, and found spontaneous development of TGM4 autoantibodies specifically in males. Aire-deficient mice failed to present TGM4 in the thymus, consistent with a defect in central tolerance for TGM4. In the mouse, we further link TGM4 immunity with a destructive prostatitis and compromised secretion of TGM4. Collectively, our findings in APS1 patients and Aire-deficient mice reveal prostate autoimmunity as a major manifestation of APS1 with potential role in male subfertility.
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| 40. |
- Lindstedt Ingemansson, Sandra, et al.
(författare)
-
Comparative outcome of double lung transplantation using conventional donor lungs and non-acceptable donor lungs reconditioned ex vivo.
- 2010
-
Ingår i: Interactive Cardiovascular and Thoracic Surgery. - : Oxford University Press (OUP). - 1569-9285 .- 1569-9293.
-
Tidskriftsartikel (refereegranskat)abstract
- A method to evaluate and recondition lungs ex vivo has been tested on donor lungs that have been rejected for transplantation. In the present paper, we compare early postoperative course between the six patients who received reconditioned lungs and the patients who received conventional donor lungs during the same period of time. During 2006 and 2007, a total of 21 patients underwent double sequential lung transplantation at the University Hospital of Lund. Six of those patients received reconditioned lungs. The other 15 patients received conventional donor lungs for transplantation without reconditioning ex vivo. The results are presented as median and interquartile range. Time in intensive care unit (days) between recipients of reconditioned lungs [13 (5-24) days], and recipients of conventional donor lungs [7 (5-12) days], P=0.44. Total hospital stay after transplantation (days) between recipients of reconditioned lungs [52 (47-60) days] and recipients of conventional donor lungs [44 (37-48) days], P=0.9. Ex vivo lung evaluation and reconditioning might not prolong early postoperative course in double lung transplantation. However, given the small number of patients, there might be a failure to detect a difference between the two groups. Keywords: Double lung transplantation; Reconditioned lungs; Clinical outcome.
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| 41. |
- Lindstedt Ingemansson, Sandra, et al.
(författare)
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How to recondition ex vivo initially rejected donor lungs for clinical transplantation: clinical experience from lund university hospital.
- 2011
-
Ingår i: Journal of transplantation. - : Hindawi Limited. - 2090-0015 .- 2090-0007. ; 2011:Aug 24
-
Tidskriftsartikel (refereegranskat)abstract
- A major problem in clinical lung transplantation is the shortage of donor lungs. Only about 20% of donor lungs are accepted for transplantation. We have recently reported the results of the first six double lung transplantations performed with donor lungs reconditioned ex vivo that had been deemed unsuitable for transplantation by the Scandiatransplant, Eurotransplant, and UK Transplant organizations because the arterial oxygen pressure was less than 40 kPa. The three-month survival of patients undergoing transplant with these lungs was 100%. One patient died due to sepsis after 95 days, and one due to rejection after 9 months. Four recipients are still alive and well 24 months after transplantation, with no signs of bronchiolitis obliterans syndrome. The donor lungs were reconditioned ex vivo in an extracorporeal membrane oxygenation circuit using STEEN solution mixed with erythrocytes, to dehydrate edematous lung tissue. Functional evaluation was performed with deoxygenated perfusate at different inspired fractions of oxygen. The arterial oxygen pressure was significantly improved in this model. This ex vivo evaluation model is thus a valuable addition to the armamentarium in increasing the number of acceptable lungs in a donor population with inferior arterial oxygen pressure values, thereby, increasing the lung donor pool for transplantation. In the following paper we present our clinical experience from the first six patients in the world. We also present the technique we used in detail with flowchart.
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| 42. |
- Lindstedt Ingemansson, Sandra, et al.
(författare)
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Impact of different topical negative pressure levels on myocardial microvascular blood flow.
- 2008
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Ingår i: Cardiovascular Revascularization Medicine. - : Elsevier BV. - 1878-0938 .- 1553-8389. ; 9:1, s. 29-35
-
Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: We have previously shown that a myocardial topical negative pressure (TNP) of -50 mmHg significantly increases microvascular blood flow in the underlying myocardium in normal, ischemic, and reperfused porcine myocardium. The present study was designed to elucidate the effect of different TNP levels between -50 and -150 mmHg on microvascular flow in normal and ischemic myocardium. MATERIALS AND METHODS: Seven pigs underwent median sternotomy. The microvascular blood flow in the myocardium was recorded, before and after the application of TNP, using laser Doppler velocimetry. Analyses were performed before left anterior descending artery (LAD) occlusion (normal myocardium) and after 20 min of LAD occlusion (ischemic myocardium). RESULTS: A TNP of -50 mmHg significantly increased microvascular blood flow in both normal (from 320.0+/-56.1 PU before TNP application to 435.7+/-65.5 PU after TNP application, P=.028) and ischemic myocardium (from 110.0+/-36.7 PU before TNP application to 194.3+/-56.2 PU after TNP application, P=.012). TNP between -75 and -150 mmHg showed no significant increase in microvascular blood flow in normal or ischemic myocardium. CONCLUSIONS: Of pressures between -50 and -150 mmHg, a TNP of -50 mmHg seems to be the most effective negative pressure concerning significant increase in microvascular blood flow in both normal and ischemic myocardium.
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| 43. |
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| 44. |
- Lindstedt, Sandra, et al.
(författare)
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Lung transplant after 6 months on ECMO support for SARS-CoV-2-induced ARDS complicated by severe antibody-mediated rejection
- 2021
-
Ingår i: BMJ Open Respiratory Research. - : BMJ. - 2052-4439. ; 8, s. 1-4
-
Tidskriftsartikel (refereegranskat)abstract
- There have been a few reports of successful lung transplantation (LTx) in patients with SARS-CoV-2-induced acute respiratory distress syndrome (ARDS); however, all reports were with rather short follow-up. Here we present a 62-year-old man without prior lung diseases. Following SARS-CoV-2-induced ARDS and 6 months of extracorporeal membrane oxygenation, he underwent LTx. 3 months post-transplantation he developed acute hypoxia requiring emergency intubation. Chest imaging showed acute rejection, and de novo DQ8-DSA was discovered. He was treated with a high dose of corticosteroids and plasmapheresis and was extubated 4 days later, yet the de novo DQ8-DSA remained. After sessions of plasmapheresis and rituximab, the levels of de novo DQ8-DSA remained unchanged. Nine months post-transplantation the patient died of respiratory failure. We herein discuss the decision to transplant, the transplantation itself and the postoperative course with severe antibody-mediated rejection. In addition, we evaluated the histological changes of the explanted lungs and compared these with end-stage idiopathic pulmonary fibrosis tissue, where both similarities and differences are seen. With the current case experience, one might consider close monitoring regarding DSA, and gives further support that LTx should only be considered for very carefully selected patients.
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| 45. |
- Lundholm, Lovisa, et al.
(författare)
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Effects of estrogen on gene expression profiles in mouse hypothalamus and white adipose tissue: target genes include glutathione peroxidase 3 and cell death-inducing DNA fragmentation factor, alpha-subunit-like effector A.
- 2008
-
Ingår i: The Journal of endocrinology. - 1479-6805. ; 196:3, s. 547-57
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Tidskriftsartikel (refereegranskat)abstract
- Obesity has become a major health problem in many parts of the world. Estrogens are known to reduce adipose tissue mass in both humans and animals but the molecular mechanisms are not well characterized. We used gene expression profiling to study long-term effects of estrogen on gene expression in mouse white adipose tissue and hypothalamus. Overall, the effects of estrogen on hypothalamic gene expression were much smaller than the corresponding effects on white adipose tissue gene expression. We characterize in detail estrogenic regulation of glutathione peroxidase 3 (GPX3). Our studies suggest that GPX3 is a direct estrogen receptor alpha target gene in white adipose tissue. Since obesity is correlated with oxidative stress, and GPX3 has been demonstrated to be lower in obesity and higher after weight loss, we hypothesize that GPX3 is one important mediator of effects of estrogen in relation to fat mass. Additional genes that were affected by estrogen in adipose tissue include cell death-inducing DNA fragmentation factor, alpha-subunit-like effector A (CIDEA), a gene shown to be related to body fat in mice. We conclude that estrogen has large effects on gene expression in white adipose tissue and hypothesize that GPX3 and CIDEA could be important mediators of the effects of estrogen on fat mass.
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| 46. |
- Magnusson, Rasmus, et al.
(författare)
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RNA-sequencing and mass-spectrometry proteomic time-series analysis of T-cell differentiation identified multiple splice variants models that predicted validated protein biomarkers in inflammatory diseases
- 2022
-
Ingår i: Frontiers in Molecular Biosciences. - : Frontiers Media SA. - 2296-889X. ; 9
-
Tidskriftsartikel (refereegranskat)abstract
- Profiling of mRNA expression is an important method to identify biomarkers but complicated by limited correlations between mRNA expression and protein abundance. We hypothesised that these correlations could be improved by mathematical models based on measuring splice variants and time delay in protein translation. We characterised time-series of primary human naive CD4(+) T cells during early T helper type 1 differentiation with RNA-sequencing and mass-spectrometry proteomics. We performed computational time-series analysis in this system and in two other key human and murine immune cell types. Linear mathematical mixed time delayed splice variant models were used to predict protein abundances, and the models were validated using out-of-sample predictions. Lastly, we re-analysed RNA-seq datasets to evaluate biomarker discovery in five T-cell associated diseases, further validating the findings for multiple sclerosis (MS) and asthma. The new models significantly out-performing models not including the usage of multiple splice variants and time delays, as shown in cross-validation tests. Our mathematical models provided more differentially expressed proteins between patients and controls in all five diseases. Moreover, analysis of these proteins in asthma and MS supported their relevance. One marker, sCD27, was validated in MS using two independent cohorts for evaluating response to treatment and disease prognosis. In summary, our splice variant and time delay models substantially improved the prediction of protein abundance from mRNA expression in three different immune cell types. The models provided valuable biomarker candidates, which were further validated in MS and asthma.
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| 47. |
- Malmsjö, Malin, et al.
(författare)
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Comparison of bacteria and fungus-binding mesh, foam and gauze as fillers in negative pressure wound therapy - pressure transduction, wound edge contraction, microvascular blood flow and fluid retention.
- 2013
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Ingår i: International Wound Journal. - 1742-481X. ; 10:5, s. 597-605
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Tidskriftsartikel (refereegranskat)abstract
- Bacteria- and fungus-binding mesh binds and inactivates bacteria and fungus, which makes it interesting, alternative, wound filler for negative pressure wound therapy (NPWT). This study was conducted to compare the performance of pathogen-binding mesh, foam and gauze as wound fillers in NPWT with regard to pressure transduction, fluid retention, wound contraction and microvascular blood flow. Wounds on the backs of 16 pigs were filled with pathogen-binding mesh, foam or gauze and treated with NPWT. The immediate effects of 0, -40, -60, -80 and -120 mmHg, on pressure transduction and blood flow were examined in eight pigs using laser Doppler velocimetry. Wound contraction and fluid retention were studied during 72 hours of NPWT at -80 and -120 mmHg in the other eight pigs. Pathogen-binding mesh, gauze and foam provide similar pressure transduction to the wound bed during NPWT. Blood flow was found to decrease 0·5 cm laterally from the wound edge and increase 2·5 cm from the wound edge, but was unaltered 5·0 cm from the wound edge. The increase in blood flow was similar with all wound fillers. The decrease in blood flow was more pronounced with foam than with gauze and pathogen-binding mesh. Similarly, wound contraction was more pronounced with foam, than with gauze and pathogen-binding mesh. Wound fluid retention was the same in foam and pathogen-binding mesh, while more fluid was retained in the wound when using gauze. The blood flow 0·5-5 cm from the wound edge and the contraction of the wound during NPWT were similar when using pathogen-binding mesh and gauze. Wound fluid was efficiently removed through the pathogen-binding mesh, which may explain previous findings that granulation tissue formation is more rapid under pathogen-binding mesh than under gauze. This, in combination with its pathogen-binding properties, makes this mesh an interesting wound filler for use in NPWT.
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| 48. |
- Malmsjö, Malin, et al.
(författare)
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Negative Pressure Wound Therapy-associated Tissue Trauma and Pain: A Controlled In vivo Study Comparing Foam and Gauze Dressing Removal by Immunohistochemistry for Substance P and Calcitonin Gene-related Peptide in the Wound Edge.
- 2011
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Ingår i: Ostomy - Wound Management. - 0889-5899. ; 57:12, s. 30-35
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Tidskriftsartikel (refereegranskat)abstract
- Pain upon negative pressure wound therapy (NPWT) dressing removal has been reported and is believed to be associ- ated with the observation that granulation tissue grows into foam. Wound tissue damage upon removal of the foam may cause the reported pain. Calcitonin gene-related peptide (CGRP) and substance P are neuropeptides that cause inflam- mation and signal pain and are known to be released when tissue trauma occurs. The aim of this controlled in vivo study was to compare the expression of CGRP and substance P in the wound bed in control wounds and following NPWT and foam or gauze dressing removal. Eight pigs with two wounds each were treated with open-pore structure polyurethane foam or AMD gauze and NPWT of 0 (control) or -80 mm Hg for 72 hours. Following removal of the wound filler, the ex- pression of CGRP and substance P was measured, using arbitrary units, in sections of biopsies from the wound bed using immunofluorescence techniques. Substance P and CGRP were more abundant in the wound edge following the removal of foam than of gauze dressings and least abundant in control wounds. The immunofluorescence staining of the wound edge for CGRP was 52 ± 3 au after the removal of gauze and 97 ± 5 au after the removal of foam (P <0.001). For substance P, the staining was 55 ± 3 au after gauze removal and 95 ± 4 au after foam removal (P <0.001). CGRP and substance P staining was primarily located to nerves and leukocytes. The increase in CGRP and substance P immuno- fluorescence was especially prominent in the dermis but also was seen in subcutaneous and muscle tissue. Using gauze may be one way of reducing NPWT dressing change-related pain. New wound fillers designed to optimize granulation tissue formation and minimize pain issues presumably will be developed in the near future.
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| 49. |
- Malmsjö, Malin, et al.
(författare)
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The effects of variable, intermittent, and continuous negative pressure wound therapy, using foam or gauze, on wound contraction, granulation tissue formation, and ingrowth into the wound filler
- 2012
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Ingår i: Eplasty: Open Access Journal of Plastic and Reconstructive Surgery. - 1937-5719. ; 12
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: Negative pressure wound therapy (NPWT) is commonly used in the continuous mode. Intermittent pressure therapy (IPT) results in faster wound healing, but it often causes pain. Variable pressure therapy (VPT) has therefore been introduced to provide a smooth transition between 2 different pressure environments, thereby maintaining the negative pressure environment throughout the therapy. The aim of the present study was to examine the effects of IPT and VPT on granulation tissue formation.METHOD: A peripheral wound in a porcine model was treated for 72 hours with continuous NPWT (-80 mm Hg), IPT (0 to -80 mm Hg), or VPT (-10 to -80 mm Hg), using foam or gauze as wound filler. Wound contraction and force to remove the wound filler were measured. Biopsies from the wound bed were examined histologically for granulation tissue formation.RESULTS: Intermittent pressure therapy and VPT produced similar results. Wound contraction was more pronounced following IPT and VPT than continuous NPWT. Intermittent pressure therapy and VPT resulted in the formation of more granulation tissue than continuous NPWT. Leukocyte infiltration and tissue disorganization were more prominent after IPT and VPT than after continuous NPWT. Granulation tissue grew into foam but not into gauze, regardless of the mode of negative pressure application, and less force was needed to remove gauze than foam.CONCLUSIONS: Wound contraction and granulation tissue formation is more pronounced following IPT and VPT than continuous NPWT. Granulation tissue grows into foam but not into gauze. The choice of negative pressure mode and wound filler is crucial in clinical practice to optimize healing while minimizing pain.
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| 50. |
- Malmsjö, Malin, et al.
(författare)
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Use of bacteria- and fungus-binding mesh in negative pressure wound therapy provides significant granulation tissue without tissue ingrowth.
- 2014
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Ingår i: Eplasty: Open Access Journal of Plastic and Reconstructive Surgery. - 1937-5719. ; 14, s. 3-3
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Tidskriftsartikel (refereegranskat)abstract
- Objective: Bacteria- and fungus-binding mesh traps and inactivates bacteria and fungus, which makes it interesting, alternative, and wound filler for negative pressure wound therapy (NPWT). The aim of this study was to compare pathogen-binding mesh, black foam, and gauze in NPWT with regard to granulation tissue formation and ingrowth of wound bed tissue in the wound filler. Methods: Wounds on the backs of 8 pigs underwent 72 hours of NPWT using pathogen-binding mesh, foam, or gauze. Microdeformation of the wound bed and granulation tissue formation and the force required to remove the wound fillers was studied. Results: Pathogen-binding mesh produced more granulation tissue, leukocyte infiltration, and tissue disorganization in the wound bed than gauze, but less than foam. All 3 wound fillers caused microdeformation of the wound bed surface. Little force was required to remove pathogen-binding mesh and gauze, while considerable force was needed to remove foam. This is the result of tissue growth into the foam, but not into pathogen-binding mesh or gauze, as shown by examination of biopsy sections from the wound bed. Conclusions: This study shows that using pathogen-binding mesh as a wound filler for NPWT leads to a significant amount of granulation tissue in the wound bed, more than that with gauze, but eliminates the problems of ingrowth of the wound bed into the wound filler. Pathogen-binding mesh is thus an interesting wound filler in NPWT.
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