| 1. |
- Diaz-Guardamino, Marta, 3, et al.
(author)
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The local appropriation of warrior ideals in Late Bronze Age Europe: a review of the rock art site of Arroyo Tamujoso 8 and the ‘warrior’ stela of Cancho Roano (Badajoz, Spain) : La apropiación local de ideales guerreros en la Europa de la Edad del Bronce Final: una revisión del sitio de arte rupestre de Arroyo Tamujoso 8 y la estela de Cancho Roano (Badajoz, España)
- 2022
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In: Trabajos de prehistoria. - : Editorial CSIC. - 0082-5638 .- 1988-3218. ; 79:2, s. 329-345
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Journal article (peer-reviewed)abstract
- This study offers new insights into the local appropriation of warrior ideals in Late Bronze Age Europe. Through the new study of the carvings of Cancho Roano and Arroyo Tamujoso 8, located in Southwest Iberia and their landscape settings with state-of-the-art digital technologies, this paper unpicks some of the key idiosyncrasies of Iberian Late Bronze Age warrior iconography, revealing that responses to the warrior ideals circulating across Europe during that period were diverse. To understand the contexts of circulation and appropriation of these ideas from a local perspective, we also consider very briefly the multiscale connections in which the communities who created warrior stelae in Iberia were involved. The ultimate goal of this paper is to lay the groundwork for further work developing more detailed comparisons between Iberian warrior stelae and Swedish warrior iconography on rock art, also taking into account other evidence.
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| 2. |
- Elf, Johan, et al.
(author)
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Mesoscopic kinetics and its applications in protein synthesis
- 2005
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In: Systems Biology. - Heidelberg : Springer-Verlag GmbH. - 354022968X ; , s. 95-118
-
Book chapter (other academic/artistic)abstract
- Molecular biology emerged through unification of genetics and nucleic acid chemistry that took place with the discovery of the double helix (Watson and Crick 1953). Accordingly, molecular biology could be defined as the sum of all techniques used to perform genetic experiments by manipulating DNA. One consequence of the development of these techniques is large-scale sequencing of genomes from an ever increasing number of organisms. However, it became clear from this development that genetic information per se is not enough to grasp the most interesting functional and evolutionary aspects of cells and multi-cellular organisms. In fact, understanding how genotype leads to phenotype depends on concepts and techniques from areas that so far have been largely alien to molecular biological research, like physics, mathematics, and engineering. From the bits and pieces from these and other scientific fields new tools must be generated to make possible an understanding of the dynamic, adapting, and developing living systems that somehow take shape from the instructions given by their genomes. The growing total of these tools and their integration in experimental and theoretical approaches to understand complex biological processes in ways previously out of reach could be a way to define systems biology, in analogy with the above definition of molecular biology.
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| 3. |
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| 4. |
- Jarvius, Malin, et al.
(author)
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In situ detection of phosphorylated platelet-derived growth factor receptor beta using a generalized proximity ligation method
- 2007
-
In: Molecular & Cellular Proteomics. - 1535-9476 .- 1535-9484. ; 6:9, s. 1500-1509
-
Journal article (peer-reviewed)abstract
- Improved methods are needed for in situ characterization of post-translational modifications in cell lines and tissues. For example, it is desirable to monitor the phosphorylation status of individual receptor tyrosine kinases in samples from human tumors treated with inhibitors to evaluate therapeutic responses. Unfortunately the leading methods for observing the dynamics of tissue post-translational modifications in situ, immunohistochemistry and immunofluorescence, exhibit limited sensitivity and selectivity. Proximity ligation assay is a novel method that offers improved selectivity through the requirement of dual recognition and increased sensitivity by including DNA amplification as a component of detection of the target molecule. Here we therefore established a generalized in situ proximity ligation assay to investigate phosphorylation of platelet-derived growth factor receptor β (PDGFRβ) in cells stimulated with platelet-derived growth factor BB. Antibodies specific for immunoglobulins from different species, modified by attachment of DNA strands, were used as secondary proximity probes together with a pair of primary antibodies from the corresponding species. Dual recognition of receptors and phosphorylated sites by the primary antibodies in combination with the secondary proximity probes was used to generate circular DNA strands; this was followed by signal amplification by replicating the DNA circles via rolling circle amplification. We detected tyrosine phosphorylated PDGFRβ in human embryonic kidney cells stably overexpressing human influenza hemagglutinin-tagged human PDGFRβ in porcine aortic endothelial cells transfected with the β-receptor, but not in cells transfected with the α-receptor, and also in immortalized human foreskin fibroblasts, BJ hTert, endogenously expressing the PDGFRβ. We furthermore visualized tyrosine phosphorylated PDGFRβ in tissue sections from fresh frozen human scar tissue undergoing wound healing. The method should be of great value to study signal transduction, screen for effects of pharmacological agents, and enhance the diagnostic potential in histopathology.
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| 5. |
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| 6. |
- Stenman, Adam, et al.
(author)
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Pan-genomic sequencing reveals actionable cdkn2a/2b deletions and kataegis in anaplastic thyroid carcinoma
- 2021
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In: Cancers. - : MDPI AG. - 2072-6694. ; 13:24
-
Journal article (peer-reviewed)abstract
- Anaplastic thyroid carcinoma (ATC) is a lethal malignancy characterized by poor response to conventional therapies. Whole-genome sequencing (WGS) analyses of this tumor type are limited, and we therefore interrogated eight ATCs using WGS and RNA sequencing. Five out of eight cases (63%) displayed cyclin-dependent kinase inhibitor 2A (CDKN2A) abnormalities, either copy number loss (n = 4) or truncating mutations (n = 1). All four cases with loss of the CDKN2A locus (encoding p16 and p14arf) also exhibited loss of the neighboring CDKN2B gene (encoding p15ink4b), and displayed reduced CDKN2A/2B mRNA levels. Mutations in established ATC-related genes were observed, including TP53, BRAF, ARID1A, and RB1, and overrepresentation of mutations were also noted in 13 additional cancer genes. One of the more predominant mutational signatures was intimately coupled to the activity of Apolipoprotein B mRNA-editing enzyme, the catalytic polypeptide-like (APOBEC) family of cytidine deaminases implied in kataegis, a focal hypermutation phenotype, which was observed in 4/8 (50%) cases. We corroborate the roles of CDKN2A/2B in ATC development and identify kataegis as a recurrent phenomenon. Our findings pinpoint clinically relevant alterations, which may indicate response to CDK inhibitors, and focal hypermutational phenotypes that may be coupled to improved responses using immune checkpoint inhibitors.
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| 7. |
- Xu, Bo, 1980-, et al.
(author)
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Elucidation of the Binding Mode of the Carboxyterminal Region of Peptide YY to the Human Y-2 Receptor
- 2018
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In: Molecular Pharmacology. - : American Society for Pharmacology & Experimental Therapeutics (ASPET). - 0026-895X .- 1521-0111. ; 93:4, s. 323-334
-
Journal article (peer-reviewed)abstract
- Understanding the agonist-receptor interactions in the neuropeptide Y (NPY)/peptide YY (PYY) signaling system is fundamental for the design of novel modulators of appetite regulation. We report here the results of a multidisciplinary approach to elucidate the binding mode of the native peptide agonist PYY to the human Y2 receptor, based on computational modeling, peptide chemistry and in vitro pharmacological analyses. The preserved binding orientation proposed for full-length PYY and five analogs, truncated at the amino terminus, explains our pharmacological results where truncations of the N-terminal proline helix showed little effect on peptide affinity. This was followed by receptor mutagenesis to investigate the roles of several receptor positions suggested by the modeling. As a complement, PYY-(3-36) analogs were synthesized with modifications at different positions in the common PYY/NPY C-terminal fragment (32TRQRY36-amide). The results were assessed and interpreted by molecular dynamics and Free Energy Perturbation (FEP) simulations of selected mutants, providing a detailed map of the interactions of the PYY/NPY C-terminal fragment with the transmembrane cavity of the Y2 receptor. The amidated C-terminus would be stabilized by polar interactions with Gln2886.55 and Tyr2195.39, while Gln1303.32 contributes to interactions with Q34 in the peptide and T32 is close to the tip of TM7 in the receptor. This leaves the core, α-helix of the peptide exposed to make potential interactions with the extracellular loops. This model agrees with most experimental data available for the Y2 system and can be used as a basis for optimization of Y2 receptor agonists.
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| 8. |
- Andersson, Arne, et al.
(author)
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Amyloid Deposition in Transplanted Human Pancreatic Islets : A Conceivable Cause of Their Long-Term Failure
- 2008
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In: EXPERIMENTAL DIABETES RESEARCH. - : Hindawi Limited. - 1687-5214 .- 1687-5303. ; 2008:562985
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Journal article (peer-reviewed)abstract
- Following the encouraging report of the Edmonton group, there was a rejuvenation of the islet transplantation field. After that, more pessimistic views spread when long-term results of the clinical outcome were published. A progressive loss of the beta-cell function meant that almost all patients were back on insulin therapy after 5 years. More than 10 years ago, we demonstrated that amyloid deposits rapidly formed in human islets and in mouse islets transgenic for human IAPP when grafted into nude mice. It is, therefore, conceivable to consider amyloid formation as one potential candidate for the long-term failure. The present paper reviews attempts in our laboratories to elucidate the dynamics of and mechanisms behind the formation of amyloid in transplanted islets with special emphasis on the impact of long-term hyperglycemia.
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| 9. |
- Andrée, Martin, et al.
(author)
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Slutrapport för projektet Smart planering för byggande : Delprojekt 3 - BIM som informationsstöd för 3D fastighetsbildning
- 2018
-
Reports (other academic/artistic)abstract
- Samhällsbyggnadsprocessen behöver utvecklas och bli smartare, öppnare och mer effektiv för ett ökat bostadsbyggande. En digitalisering av samhällsbyggnadsprocessen kan ge ett effektivare samarbete mellan kommun, fastighetsägare, byggherrar, medborgare, näringsliv och myndigheter.Vid bildande av tredimensionellt avgränsade fastigheter eller fastighetsutrymmen (3D-fastigheter) behöver gränsernas läge redovisas både verbalt och i kartor och ritningar, detsamma gäller berörda rättigheter. Det är idag ofta svårt att korrekt redovisa en 3D-volym med enbart dagens pappersritningar och även svårt att läsa en registerkarta i 2D med fastigheter och rättigheter beslutade i 3D. Beslutsunderlagen i fastighetsbildnings-processen behöver bli mer enhetliga och entydiga samt fastighetsinformationen behöver bli återanvändningsbar i hela samhällsbyggnadsprocessen.I detta projekt har vi studerat informationsbehovet i de olika tidpunkterna under fastighetsbildningsprocessen för 3D-fastigheter med fokus på vem som är ansvarig för att tillhandahålla informationsunderlag för att identifiera krav på utformning av 3D-modeller (t.ex BIM) och 3D-stöd för fastighetsbildning.Internationellt finns det ett stort intresse och många frågeställningar gällande samspelet mellan BIM och Fastighetsinformation; det är däremot ganska få fall som har identifierats där man har arbetat praktiskt med BIM i relation till redovisning av 3D-fastigheter.Projektethar även tittat på behov av visualisering och tillhandahållande av fastighetsinformation i 3D, hur informationen bör utformas för att kunna tolkas korrekt samt nyttjas vidare av andra aktörer i samhällsbyggnadsprocessen.Slutsatsen i projektetär att en framtida arbetsmodell där man i samband med myndighetsutövningen för fastighetsbildning samverkar med stöd av BIM och geografisk information i ärendehandläggningen kan ge stora effekter på både myndighetens effektivitet och i ärendeutövningen och för förståelsen av fastighetbildningsbeslutet hos samtliga intressenter i processen. För att det arbete som genomförts i denna utredning skall få genomslag i den dagliga verksamheten rekommenderar vibland annatatt de statliga och kommunala lantmäterimyndigheterna arbetar vidare med att utveckla arbetsprocessen och rekommendationerna för 3D-fastighetsbildning baserat på resultatet från detta projekt och redan i dagens modell efterfrågar att man i handläggningsprocessen kan arbeta BIM-baserat även om kommande beslutshandlingar under en övergångsperiod fortfarande kommer att vara baserade på ritningsbilagor i 2D.
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| 10. |
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| 11. |
- Chisalita, Simona Ioana, et al.
(author)
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Differential lipid profile and hormonal response in type 2 diabetes by exogenous insulin aspart versus the insulin secretagogue repaglinide, at the same glycemic control
- 2009
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In: Acta Diabetologica. - : Springer Science and Business Media LLC. - 0940-5429 .- 1432-5233. ; 46:1, s. 35-42
-
Journal article (peer-reviewed)abstract
- Our aim was to study, at the same glycemic control, how treatment with either the insulin secretagogue repaglinide or exogenous insulin aspart affects endogenous insulin secretion, plasma insulin and IAPP (islet amyloid polypeptide) levels, GH-IGF (growth hormone-insulin-like growth factor) axis and plasma lipoprotein concentrations in patients with type 2 diabetes. Five patients, age 65.0 +/- A 4.1 years (mean +/- A SE), body weight 82.5 +/- A 5.0 kg, BMI (body mass index) 27.7 +/- A 1.5 kg/m(2) were treated for 10 weeks with repaglinide or insulin aspart in a randomized, cross-over study. At the end of each treatment a 24-h metabolic profile was performed. Blood glucose, C-peptide, free human insulin, free total (human and analogue) insulin, proinsulin, IAPP, IGF-I, IGFBP-1 (IGF binding protein-1), GHBP (growth hormone binding protein) and plasma lipoprotein concentrations were measured. Similar 24-h blood glucose profiles were obtained with repaglinide and insulin aspart treatment. During the repaglinide treatment, the meal related peaks of C-peptide and free human insulin were about twofold higher than during treatment with insulin aspart. Proinsulin, GHBP were higher and IAPP levels tended to be higher during repaglinide compared to insulin aspart. Postprandial plasma total cholesterol, triglycerides and apolipoprotein B concentrations were higher on repaglinide than on insulin aspart treatment. Our results show that, at the same glycemic control, treatment with exogenous insulin aspart in comparison with the insulin secretagogue repaglinide result in a lower endogenous insulin secretion, and a tendency towards a less atherogenic postprandial lipid profile.
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| 12. |
- Forslund, Ola, et al.
(author)
-
A novel human in vitro papillomavirus type 16 positive tonsil cancer cell line with high sensitivity to radiation and cisplatin
- 2019
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In: BMC Cancer. - : Springer Science and Business Media LLC. - 1471-2407. ; 19:1
-
Journal article (peer-reviewed)abstract
- Background: Human papillomavirus (HPV) is an established risk factor for oropharyngeal squamous cell carcinoma (OSCC). The aim was to establish cell lines from HPV-positive tonsil carcinomas to be used for treatment development. Methods: Fresh samples from 23 HPV-positive tonsil carcinomas were cultivated in vitro. The established cell line was analyzed for viral characteristics, cell karyotype, TP53 status, and growth capabilities in nude mice. In vitro studies of sensitivities to radiation, cisplatin and cetuximab were performed. Results: After 19 months (eight passages), one cell line, LU-HNSCC-26, was established in vitro and also grew as xenografts. The tumor was from a 48 year old non-smoking man with non-keratinizing, p16 positive tonsil OSCC, stage T2N0M0 with HPV16. It contained 19.5 (CV% 3.7) HPV16 copies/cell (passage 8). The complete HPV16 genome sequence was obtained. Episomal HPV16 was present with an E2/E7 ratio of 1.1 (CV% 2.6). In addition, HPV16 mRNA specific for the intact E2 gene was detected. The viral expression manifested 1.0 (CV% 0.1) E7 mRNA copies per HPV16 genome. The karyotype was determined and the cell line demonstrated wild type TP53. The ID50 for radiation was 0.90 Gy and the IC50 for cisplatin was 0.99 μmol/L. The cell line was inhibited to a maximum of 18% by cetuximab. Conclusions: We established an in vitro tonsil carcinoma cell line containing episomal HPV16. This is an important step towards efficient treatment development.
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| 13. |
- Gretarsson, Sigurdur, et al.
(author)
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Substantial intrinsic variability in chemoradiosensitivity of newly established anaplastic thyroid cancer cell-lines
- 2020
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In: Acta Oto-Laryngologica. - : Informa UK Limited. - 1651-2251 .- 0001-6489. ; 140:4, s. 337-343
-
Journal article (peer-reviewed)abstract
- Background: Well characterized human cell lines are needed for preclinical treatment studies of anaplastic thyroid cancer (ATC).Aims/Objectives: The aim was to establish, verify and characterize a panel of ATC cell lines.Material and methods: Cell lines were established from ATC fine-needle aspiration biopsies and characterized genetically and functionally regarding treatment sensitivities.Results: Eight cell lines were established in vitro and the anaplastic thyroid origin was verified. Seven of the cell lines were also grown as xenografts. The cell lines harboured complex karyotypes with modal numbers in hyperdiploid to near-pentaploid range. Five were TP53 mutated and three carried the BRAFV600E mutation. None had rearrangements of RET. For doxorubicin, IC50 ranged from 0.42 to 46 nmol/L and for paclitaxel from 1.6 to 196 nmol/L. Radiation sensitivity varied between 2.6 and 6.3 Gy. Two of the BRAF mutated cell lines displayed high sensitivity to vemurafenib, while the third was similar to the wild-type ones.Conclusions and significance: We describe a series of new ATC cell lines demonstrating large heterogeneity in the response to cytostatic drugs and the BRAF inhibitor vemurafenib. The observations are relevant to future attempts to optimize treatment combinations for ATC.
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| 14. |
- Hansén Nord, Karolin, et al.
(author)
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Retained heterodisomy is associated with high gene expression in hyperhaploid inflammatory leiomyosarcoma.
- 2012
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In: Neoplasia. - : Elsevier BV. - 1522-8002. ; 14:9, s. 807-U156
-
Journal article (peer-reviewed)abstract
- Inflammatory leiomyosarcoma (ILMS) is a soft tissue tumor that morphologically resembles conventional leiomyosarcoma (LMS) admixed with a prominent inflammatory infiltrate. Genetic data on ILMS are still limited but have suggested that this entity is characterized by hyperhaploidy (24-34 chromosomes). This low chromosome number is otherwise uncommon in neoplasia and has been found only in 0.2% to 0.3% of cytogenetically investigated tumors. Here, three ILMS were investigated using cytogenetic, single-nucleotide polymorphism (SNP) array, and global gene expression analyses. All cases displayed a hyperhaploid origin. Combined with previously reported cases, hyperhaploidy has been found in six of seven cytogenetically investigated ILMS. The copy number distribution of individual chromosomes is clearly nonrandom; the hyperhaploid clones of all six cases displayed disomy for chromosomes 5 and 20, and two copies of chromosomes 18, 21, and 22 were also common. All chromosomes identified as disomic showed a biparental origin by SNP array analysis; whether this is of pathogenetic importance is not known. Compared with conventional LMS, ILMS had a distinct gene expression signature. Furthermore, the number of chromosome copies correlated well with gene expression levels; disomic chromosomes showed higher gene expression levels than monosomic chromosomes, a finding that has not previously been reported for hyperhaploid tumors. Taken together, our findings suggest that disomy for some chromosomes, notably 5 and 20, as well as distorted gene expression achieved through massive loss of other chromosomes are essential features of ILMS.
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| 15. |
- Jason, Johan, et al.
(author)
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Fiber-Optic Temperature Monitoring in Pulp Production
- 2008
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In: Transactions of the IWCS. - Eatontown, NJ : International Wire & Cable Symposium. ; , s. 7-16
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Conference paper (peer-reviewed)abstract
- A fiber-optic temperature sensor system for monitoring of the cooking process in pulp production has been developed. The sensor system is based on intensity modulation in mechanical fiber connections caused by the temperature dependent deflection of a bimetal strip. The sensor construction includes a fiber positioning device which eliminates the poor coupling efficiency otherwise experienced with coupling based sensors. An OTDR-based control unit monitors the changes in optical power at the sensor points, and the sensor network is realized with blown fiber. The total system is thus a very cost-effective solution. In this paper the development, testing, installation and operation of the sensor system is reported on, showing the system to be suitable for cooking process temperature monitoring.
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| 16. |
- Jason, Johan, et al.
(author)
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Fiber-Optic Temperature Monitoring in Pulp Production
- 2006
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In: Proceedings of the 55th IWCS/Focus Conference. - Eatontown, NJ : International Wire & Cable Symposium. ; , s. 41-49
-
Conference paper (other academic/artistic)abstract
- A fiber-optic temperature sensor system has been developed and implemented in the monitoring of the cooking process in pulp production. The sensor system is based on intensity modulation in mechanical multimode fiber connections caused by the temperature dependent deflection of a bimetal strip. OTDR technology is used for monitoring the changes in optical power at the sensor points in the network, and a computer system takes care of calibration curves and the power-to-temperature conversion. Fiber segments between the sensor points and the control unit are realized with blown fiber. In this paper, the development and testing of the temperature monitoring system is reported on. Sensor performance, data readout, installation issues and measurement results are discussed. The system is shown to meet the requirements on precision and response time and to be a useful tool for the monitoring of the cooking process.
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| 17. |
- Jason, Johan, et al.
(author)
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Fibre-to-the-Sensor - Blown Fibre Technology in Fibre-Optic Sensor Networks
- 2007
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In: NOC 2007 Proceedings : 12th European Conference on Networks and Optical Communications incorporating papers of Conference on Optical Cabling and Infrastructure - OC & I. - Kista-Stockholm : Acreo. ; , s. 649-
-
Conference paper (other academic/artistic)abstract
- In this paper the use of blown fibre technology in fibre-optic sensing is discussed. Starting with a background in sensor network topologies and distributed sensor technology, realised and potential applications in industry and society are presented and discussed. The examples mentioned suggest blown fibre as an attractive approach when planning and installing a fibre-optic sensor network. Also, blown distributed fibre sensor units are proposed for use in existing microduct infrastructure.
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| 18. |
- Lalwani, Shruti, et al.
(author)
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Changes in nutritional and technological properties of heat-treated milk and cream at dairy production scale during storage
- 2024
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In: International Dairy Journal. - 0958-6946. ; 154
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Journal article (peer-reviewed)abstract
- Changes in nutritional and technological properties during storage of milk and cream subjected to different heat treatments at dairy production scale (high-temperature-short-time pasteurisation, extended shelf-life treatment and ultra-high temperature treatment) were investigated. Results indicate a decrease in pH with longer storage times, whereas no changes in ionic calcium concentration occurred during shorter storage. Vitamin losses ranged from 1 to 22% for different heat treatments and more pronounced effects of vitamin degradation was observed with more intense heat treatment and longer storage times. Vitamin B12 concentration tended to decrease more over time than vitamins B1, B2 and E and more losses in vitamin concentration were found after storage than after heat treatment. Significant effects on physical stability and colour changes in milk and cream were observed during prolonged storage. This suggests that larger changes in nutritional and technological quality of heat-treated milk and cream at dairy production scale occur during longer storage times.
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| 19. |
- Lalwani, Shruti, et al.
(author)
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Impact of thermal processing on micronutrients and physical stability of milk and cream at dairy production scale
- 2024
-
In: International Dairy Journal. - 0958-6946. ; 153
-
Journal article (peer-reviewed)abstract
- Micronutrients and physical stability of milk and cream were evaluated for different heat treatments at dairy production scale (HTST pasteurisation, high pasteurisation, ESL indirect and UHT direct and indirect). Changes caused due to heat treatments for macro and micro components (vitamins and minerals) as well as physical stability were investigated. Results show limited losses in macro components and total mineral concentrations for milk and cream after the studied heat treatments. Significant decrease in concentrations of vitamins B1, B2 and B12 and ionic calcium in milk was observed after high pasteurisation, whereas limited losses were observed after ESL and UHT processing. Casein micelle size in milk increased, however, no effect on physical stability was observed between heat treatments. This work shows that heating technologies at industrial dairy production scale investigated were mild and have low effects on micronutrients and physical stability of milk and cream.
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| 20. |
- Lind, Anna, et al.
(author)
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Regional myo-inositol, creatine and choline levels are higher at older age and scale negatively with visuo-spatial working memory : a cross-sectional proton MR spectroscopy study at 7 tesla on normal ageing
- 2020
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In: Journal of Neuroscience. - : The Society for Neuroscience. - 0270-6474 .- 1529-2401. ; 40:42, s. 8149-8159
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Journal article (peer-reviewed)abstract
- Proton MR spectroscopy (1H-MRS) has been used to assess regional neurochemical brain changes during normal ageing, but results have varied. Exploiting the increased sensitivity at ultra-high field, we performed 1H-MRS in 60 healthy human volunteers to asses age-related differences in metabolite levels and their relation to cognitive ageing. Sex was balanced, and participants were assigned to a younger, middle, and older group according to their age, ranging from 18 to 79 years. They underwent 7T 1H-MRS of the ACC, DLPFC, hippocampus, and thalamus and performed a visuospatial working memory task outside the scanner. A multivariate ANCOVA revealed a significant overall effect of age group on metabolite levels in all regions. Higher levels in the middle than the younger group were observed for myo-inositol (mIns) in DLPFC and hippocampus and total choline (tCho) in ACC. Higher levels in the older than the younger group were observed for mIns in hippocampus and thalamus, total creatine (tCr) and tCho in ACC and hippocampus; lower levels of glutamate (Glu) were observed in DLPFC. Higher levels in the older than the middle group were observed for mIns in hippocampus, tCr in ACC and hippocampus, tCho in hippocampus, and total N-acetyl aspartate (tNAA) in hippocampus. Working memory performance correlated negatively with tCr and tCho levels in ACC and mIns levels in hippocampus and thalamus, but not with tNAA or glutamate levels. As NAA and Glu are commonly regarded to reflect neuronal health and function and concentrations of mIns, tCr, and tCho are higher in glia than neurons, the findings of this study suggest a potential in vivo connection between cognitive ageing and higher regional levels of glia-related metabolites.SIGNIFICANCE STATEMENT Neurochemical ageing is an integral component of age-related cognitive decline. Proton MR spectroscopy (1H-MRS) studies of in vivo neurochemical changes across the lifespan have, however, yielded inconclusive results. 1H-MRS at ultra-high field strength can potentially improve the consistency of findings. Using 7T 1H-MRS, we assessed levels of mIns, tCr, and tCho (glia-related metabolites) and tNAA and Glu (neuron-related metabolites) in ACC, DLPFC, hippocampus, and thalamus. We found higher levels of glia-related metabolites in all brain regions in older individuals. Working memory performance correlated negatively with regional levels of glia-related metabolites. This study is the first to investigate normal ageing in these brain regions using 7T 1H-MRS and findings indicate that glia-related metabolites could be valuable in cognitive ageing studies
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| 21. |
- Nilsson, Johan, et al.
(author)
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A randomized study of coronary artery bypass surgery performed with the Resting Heart™ System utilizing a low vs a standard dosage of heparin.
- 2012
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In: Interactive Cardiovascular and Thoracic Surgery. - : Oxford University Press (OUP). - 1569-9285 .- 1569-9293. ; 15:5, s. 834-839
-
Journal article (peer-reviewed)abstract
- OBJECTIVES: Allogeneic blood transfusion and reoperation for postoperative bleeding after the coronary artery bypass grafting have a negative impact on the patient outcome. This study aimed at evaluating the effects of reduced doses of heparin and protamine on the patient outcome, using a heparin-coated mini-cardiopulmonary bypass (CPB) system. METHODS: Sixty patients undergoing elective first-time CPB were prospectively randomized either to have a reduced systemic heparinization [activated clotting time (ACT) = 250 s] or to a control group perfused with a full heparin dose (ACT = 420 s). Blood transfusions, ventilation time, early postoperative bleeding, ICU stay, reoperations for bleeding, postoperative cognitive status and the level of mobilization were registered. RESULTS: Twenty-nine patients were randomized to the control group, 27 patients to the low-dose group and 4 patients were excluded because of protocol violations. Four patients in the control group received a total of 10 units of packed red blood cells, and in the low-dose group, no transfusions were given, P = 0.046. No patient was reoperated because of bleeding. The ICU stay was significantly shorter in the low-dose group (8.4 vs 13.7 h, P = 0.020), less dependent on oxygen on the first postoperative day (78 vs 97%, P = 0.034), better mobilized (89 vs 59%, P = 0.006) and had less pain (visual analogue scale 2.0 vs 3.5, P = 0.019) compared with the control group. CONCLUSIONS: The use of a mini-CPB system combined with a low dose of heparin reduced the need for blood transfusions and may facilitate the faster mobilization of the patients.
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| 22. |
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| 23. |
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| 24. |
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| 25. |
- Oskarsson, Marie E., et al.
(author)
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In Vivo Seeding and Cross-Seeding of Localized Amyloidosis A Molecular Link between Type 2 Diabetes and Alzheimer Disease
- 2015
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In: American Journal of Pathology. - : Elsevier BV. - 0002-9440 .- 1525-2191. ; 185:3, s. 834-846
-
Journal article (peer-reviewed)abstract
- Several proteins have been identified as amyloid forming in humans, and independent of protein origin, the fibrils are morphologically similar. Therefore, there is a potential for structures with amyloid seeding ability to induce both homologous and heterologous fibril growth; thus, molecular interaction can constitute a Link between different amyloid forms. Intravenous injection with preformed fibrils from islet amyloid polypeptide (IAPP), proIAPP, or amyloid-beta (A beta) into human IAPP transgenic mice triggered IAPP amyloid formation in pancreas in 5 of 7 mice in each group, demonstrating that IAPP amyloid could be enhanced through homologous and heterologous seeding with higher efficiency for the former mechanism. Proximity Ligation assay was used for colocalization studies of IAPP and A beta in islet amyloid in type 2 diabetic patients and A beta deposits in brains of patients with Alzheimer disease. All reactivity was not detected in islet amyloid although islet beta cells express A beta PP and convertases necessary for A beta production. By contrast, IAPP and proIAPP were detected in cerebral and vascular A beta deposits, and presence of proximity Ligation signal at both locations showed that the peptides were <40 nm apart. It is not clear whether IAPP present in brain originates from pancreas or is Locally produced. Heterologous seeding between IAPP and All shown here may represent a molecular Link between type 2 diabetes and Alzheimer disease.
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| 26. |
- Paulsson, Johan, 1976-, et al.
(author)
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Aberrant processing of human proislet amyloid polypeptide results in increased amyloid formation
- 2005
-
In: Diabetes. - : American Diabetes Association. - 0012-1797 .- 1939-327X. ; 54:7, s. 2117-2125
-
Journal article (peer-reviewed)abstract
- The amyloid present in the islets of Langerhans in type 2 diabetes is polymerized islet amyloid polypeptide (IAPP). The precursor protein proIAPP is posttranslationally modified, a process involving the removal of NH2- and COOH-terminal flanking peptides. This step is performed by the prohormone convertases PC2 and PC1/3. PC2 processes proIAPP preferably at the NH 2-terminal processing site, and PC1/3 processes proIAPP exclusively at the COOH-terminal site. Little is known regarding the exact circumstances leading to islet amyloid formation. In this study, we have examined the possible significance of aberrant processing of proIAPP on amyloid formation in several in vitro cellular systems. In our studies, human (h)-proIAPP was transfected into β-TC-6 cells expressing both prohormone convertases and in which proIAPP is processed into IAPP. Additionally, h-proIAPP was transfected into three different pituitary-derived cell lines with different prohormone convertase profiles: AtT-20 cells (deficient in PC2), GH3 cells (deficient in PC1/3), and GH4C1 cells (deficient in both convertases). We followed the processing of h-proIAPP with antibodies specific for the respective cleavage sites and stained the cells with Congo red to verify the accumulation of amyloid. Incomplete processing of h-proIAPP that occurs in AtT-20 and GH4C1 cells resulted in the formation of intracellular amyloid. No amyloid developed in β-TC-6 and GH3 cells lines with full processing of proIAPP. An intracellular increase in proIAPP and/or its metabolic products may thus promote intracellular amyloid formation, thereby causing cell death. When extracellularly exposed, this amyloid might act as template for continuing amyloid formation from processed IAPP released from the surrounding β-cells. © 2005 by the American Diabetes Association.
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| 27. |
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| 28. |
- Paulsson, Johan F., 1976-
(author)
-
Proislet Amyloid Polypeptide (proIAPP) : Impaired Processing is an Important Factor in Early Amyloidogenesis in Type 2 Diabetes
- 2006
-
Doctoral thesis (other academic/artistic)abstract
- Amyloid is defined as extracellular protein aggregates with a characteristic fibrillar ultra-structure, Congo red affinity and a unique x-ray diffraction pattern. At present, 25 different human amyloid fibril proteins have been identified, and amyloid aggregation is associated with pathological manifestations such as Alzheimer’s disease, spongiform encephalopathy and type 2 diabetes. Amyloid aggregation triggers apoptosis by incorporation of early oligomers in cellular membranes, causing influx of ions. Amyloid is the only visible pathological islet alteration in subjects with type 2 diabetes, and islet amyloid polypeptide (IAPP) is the major islet amyloid fibril component. IAPP is produced by beta-cells and co-localized with insulin in the secretory granules. Both peptides are synthesised as pro-molecules and undergo proteolytic cleavage by the prohormone convertase 1/3 and 2. Although IAPP is the main amyloid constituent, both proIAPP and proIAPP processing intermediates have been identified in islet amyloid.The aim of this thesis was to study the role of impaired processing of human proIAPP in early islet amyloidogenesis. Five cell lines with individual processing properties were transfected with human proIAPP and expression, aggregation and viability were studied. Cells unable to process proIAPP into IAPP or to process proIAPP at the N-terminal processing site accumulated intracellular amyloid-like aggregates and underwent apoptosis. Further, proIAPP immunoreactivity was detected in intracellular amyloid-like aggregates in betacells from transgenic mice expressing human IAPP and in transplanted human beta-cells. ProIAPP was hypothesized to act as a nidus for further islet amyloid deposition, and to investigate this theory, amyloid-like fibrils produced from recombinant IAPP, proIAPP and insulin C-peptide/A-chain were injected in the tail vein of transgenic mice expressing the gene for human IAPP. Pancreata were recovered after 10 months and analysed for the presence of amyloid. Both IAPP and proIAPP fibrils but not des-31,32 proinsulin fibrils, caused an increase in affected islets and also an increase of the amyloid amount. This finding demonstrates a seeding capacity of proIAPP on IAPP fibrillogenesis. IAPP has been known for some time to trigger apoptosis in cultured cells, and a novel method for real time detection of apoptosis in beta-cells was developed. Aggregation of recombinant proIAPP and proIAPP processing intermediates were concluded to be inducers of apoptosis as potent as IAPP fibril formation.From the results of this study, a scenario for initial islet amyloidogenesis is proposed. Initial amyloid formation occurs intracellularly as a result of alterations in beta-cell processing capacity. When the host cell undergoes apoptosis intracellular proIAPP amyloid becomes extracellular and can act as seed for further islet amyloid deposition.
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| 29. |
- Paulsson, Johan F, et al.
(author)
-
Real-Time Monitoring of Apoptosis by Caspase-3-Like Protease Induced FRET Reduction Triggered by Amyloid Aggregation
- 2008
-
In: Experimental Diabetes Research. - : Hindawi Limited. - 1687-5214 .- 1687-5303. ; 2008:865850
-
Journal article (peer-reviewed)abstract
- Amyloid formation is cytotoxic and can activate the caspase cascade. Here, we monitor caspase-3-like activity as reduction of fluorescence resonance energy transfer (FRET) using the contstruct pFRET2-DEVD containing enhanced cyan fluorescent protin (EYFP) linked by the caspase-3 specific cleavage site residues DEVD. Beta-TC-6 cells were transfected, and the fluoorescence was measured at 440 nm excitation and 535 nm (EYFP) and 480 nm (ECFP) emission wavelength. Cells were incubated with recombinant pro lset Amyloid Polypeptide (rec prolAPP) or the processing metabolites of prolAPP; the N-terminal flanking peptide withIAPP (recN+IAPP); IAPP with the C-terminal flanking peptied (recIAPP+C) and lslet Amyloid Polypeptide (recIAPP). Peptides were added in solubilized from (50 mu M) or as performed amyloid-like fibrils, or as a combination of these. FRET was measured and incubation with a mixture of solubilized peptide and performed fibrils resulted in loss of FRET and apoptosis was determined to occurein cells incubated with recproIAPP (49%), recN+IAPP (46%), recIAPP (72%) and recIAPP+C (59%). These results show that proIAPP and the processing intermediates reside the same cell toxic capacity as IAPP, and they can all have a central role in the reduction of beta-cell number in type 2 diabetes.
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| 30. |
- Paulsson, Johan F, et al.
(author)
-
There is a role for proIAPP in islet amyloid fibrillogenesis
- 2008
-
Other publication (other academic/artistic)abstract
- Islet amyloid polypeptide (IAPP) can aggregate into amyloid, a common pathological finding present extracellularly in the islets of Langerhans in individuals with type 2 diabetes. IAPP arises from posttranslational processing of the precursor proIAPP. Accumulation of proIAPP in the secretory granules can result in proIAPP-amyloid formation. We raise the following hypothesis; proIAPP can under not yet defined circumstances aggregate into amyloid-like fibrils intracellularly and at this location act as template and cross-seed amyloid formation of IAPP. We have produced recombinant peptides corresponding to proIAPP and IAPP. These peptides aggregate readily into fibrils with typical amyloid characteristics. Sonicated recproIAPP- and recIAPP- preformed fibrillar aggregates were injected intravenously to +/hIAPP/-mIAPP transgenic mice. Male mice from this strain develop islet amyloid in response to high fat diet. Control animals received an injection of preformed amyloid fibrils from the proinsulin processing intermediate (C-peptide/A-chain) or sodium chloride. All animals were fed a diet high in fat over a ten month period. The presence of islet amyloid was studied after Congo red staining. We found amyloid in 20 % of the islets in animals injected with preformed recIAPP fibrils and in 10 % of the islets in animals injected with preformed recproIAPP fibrils. Control animals developed amyloid in 1-2% of the islets. Our results support the hypothesis that proIAPP-fibrils can act as template and induce conformational changes in soluble IAPP that results in propagation of the amyloid fibrils. This is the first report on in vivo seeding of a localized amyloid form and we present data that support transport of amyloid between islets as a putative route for the spreading of islet amyloid. Our finding suggests that therapies, which use capping of fibril endings, might be useless.
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| 31. |
- Paulsson, Johan
(author)
-
Genetic and molecular characterization of follicular thyroid tumors : diagnostic and prognostic aspects
- 2021
-
Doctoral thesis (other academic/artistic)abstract
- Follicular thyroid carcinoma (FTC) is the second most common thyroid malignancy and it sometimes metastasize to lungs and bone. A substantial subset of these tumors lacks an identified driver event and no well-established prognostic and diagnostic markers exist. Also, to distinguish this malignant tumor from benign follicular thyroid adenoma (FTA) and from follicular tumor with uncertain malignant potential (FT-UMP) patients need to undergo a diagnostic hemithyroidectomy for histopathological analysis. The aim of this thesis was to further clarify the molecular and genetic background of follicular thyroid tumors to facilitate diagnosis and prognostication. In Paper I, high frequencies of TERT promoter mutations, copy number (CN) gains, mRNA expression and hypermethylation in FTC were identified. Almost all tumors with TERT mRNA expression had one of the TERT alterations (mutation, CN gain or hypermethylation) which suggests that not only TERT promoter mutation can augment expression. Remarkably, similar high frequencies of these alterations were observed in FT-UMP but not in FTA. Given the intimate association of TERT alterations to a worse clinical outcome, this suggests that subsets of FT-UMPs do have malignant potential. Furthermore, these alterations could be used to pinpoint FTC with a poorer prognosis and to distinguish between FTA and FTC/FT-UMP. Paper II focused on TERT promoter mutated FT-UMPs and the possible link to malignant potential. A clinical follow-up of 51 cases of FT-UMPs was performed. In total, 16% of these cases had a TERT promoter mutation and 37% of these mutated cases recurred with metastatic disease. The disease-free survival for the mutated FT-UMP patients was similar as for the TERT promoter mutated minimally invasive FTC (miFTC), but significantly shorter than TERT wildtype miFTC. These results indicate that FT-UMPs with TERT promoter mutations harbor malignant potential. Treatment and follow-up strategies should therefore be similar as for malignant tumors. In Paper III, whole-exome sequencing (WES) was used to search for novel FTC driver events and to identify genetic signatures that could distinguish between the FTC histological subtypes: widely invasive FTC (wiFTC), encapsulated angioinvasive (eaiFTC) and miFTC. Recurrent mutations were identified in TSHR, DICER1, EIF1AX, KDM5C, NF1, PTEN, and TP53. Interestingly, there was no difference in the mutational burden across the subtypes. However, higher mutational burden was a risk factor for worse clinical outcome independent of histologic subtype. In Paper IV, the occurrence of DICER1 alterations and how this gene is regulated in FTC and the related Hürthle cell carcinoma (HCC) was explored. Mutations were rare but did occur in subset of young patients. However, there was a general downregulation in carcinomas compared with adenomas. The DICER1 mRNA expression was strongly correlated with the transcription factor GABPA mRNA expression suggesting an interaction. In vitro experiments verified that GABPA binds to the DICER1 promoter and regulates its expression. Furthermore, reduced DICER1 expression stimulated cell proliferation and disrupted the miRNA machinery. In Paper V, whole-genome sequencing and transcriptome sequencing was used to identify novel driver events in clinically aggressive FTC and HCC. A recurrent mutation (p.E518K) in the DGCR8 gene, a miRNA processing subunit, was identified. This particular mutation is known to cause early onset familial multinodular goiter and other tumors when present in germline DNA. In an extended cohort, no further mutations were evident in thyroid carcinomas, however, the expression was significantly reduced in FTC compared with FTA, suggesting an important role in tumorigenesis. The DGCR8 mutated cases and subsets of cases with low DGCR8 expression showed a specific miRNA profile and appeared in the same cluster in a hierarchical cluster analysis. Furthermore, this caused downregulation of specific mRNAs and miRNAs that could be involved in progression and metastasis of these tumors. Copy number analysis revealed recurrent gains on chromosomes 4, 6, and 10. The transcriptome analysis showed that the study cohort of 13 tumors amassed in two principal clusters. In conclusion, TERT alterations in follicular tumors can be used for diagnostic and prognostic purposes, and genetic alterations that disrupt the miRNA machinery seem to constitute an important mechanism in these cancers.
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| 32. |
- Paulsson, Johan, et al.
(author)
-
High Plasma Levels of Islet Amyloid Polypeptide in Young with New-Onset of Type 1 Diabetes Mellitus
- 2014
-
In: PLOS ONE. - : Public Library of Science. - 1932-6203. ; 9:3, s. 0093053-
-
Journal article (peer-reviewed)abstract
- Aims/Hypothesis: Islet amyloid polypeptide (IAPP) is a beta cell hormone secreted together with insulin upon glucose stimulation. IAPP participates in normal glucose regulation, but IAPP is also known for its ability to misfold and form islet amyloid. Amyloid fibrils form through smaller cell toxic intermediates and deposited amyloid disrupts normal islet architecture. Even though IAPP and amyloid formation are much discussed in type 2 diabetes, our aim was to study the significance of IAPP in type 1 diabetes. Results: Plasma IAPP levels in children and adolescents with newly diagnosed type 1 diabetes (n = 224) were analysed and concentrations exceeding 100 pmol/L (127.2 - 888.7 pmol/L) were found in 11% (25/224). The IAPP increase did not correlate with C-peptide levels. Conclusions/Interpretation: Plasma levels of IAPP and insulin deviate in a subpopulation of young with newly-diagnosed type 1 diabetes. The determined elevated levels of IAPP might increase the risk for IAPP misfolding and formation of cell toxic amyloid in beta cells. This finding add IAPP-aggregation to the list over putative pathological factors causing type 1 diabetes.
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| 33. |
- Paulsson, Johan, 1976-, et al.
(author)
-
Intracellular amyloid-like deposits contain unprocessed pro-islet amyloid polypeptide (proIAPP) in beta cells of transgenic mice overexpressing the gene for human IAPP and transplanted human islets
- 2006
-
In: Diabetologia. - : Springer Science and Business Media LLC. - 0012-186X .- 1432-0428. ; 49:6, s. 1237-1246
-
Journal article (peer-reviewed)abstract
- Aims/hypothesis: Islet amyloid is a frequent finding in the islets of Langerhans of individuals with type 2 diabetes. The main amyloid constituent is the beta cell-derived polypeptide hormone islet amyloid polypeptide (IAPP). In general, amyloid refers to an extracellular deposit of a congophilic material, but intracellular amyloid is seen in some beta cells of transgenic mice expressing the gene for human IAPP and in human islets transplanted into nude mice. The aim of this study was to immunohistochemically characterise the intracellular amyloid. Methods: Antisera against the N- and C-terminal processing sites of proIAPP (which were therefore specific for proIAPP), the C-terminal flanking peptide and mature IAPP were used for immunoelectron microscopy. Results: Fibrillar aggregates were seen in the halo region of the secretory granules in some beta cells in human IAPP transgenic mice. These aggregates were labelled with proIAPP-specific antisera. Also, proIAPP reactivity was more widespread in the intracellular amyloid-like aggregates in beta cells of transgenic mice than in human islet transplants, in which the intracellular amyloid-like deposits were larger, but the proIAPP labelling was restricted to small spots within the amyloid deposits. Conclusions/ interpretation: We suggest that proIAPP forms the first amyloid fibrils and that this can occur already in the secretory granules of the beta cells. The proIAPP-derived fibrils can act as seed for further amyloid formation, now made up by IAPP. The observed difference between human islet transplants and human IAPP transgenic animals may reflect differences in stages of amyloid development. © Springer-Verlag 2006.
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| 34. |
- Paulsson, Johan O., et al.
(author)
-
Editorial Material: Absence of the BRAF V600E mutation in pheochromocytoma in JOURNAL OF ENDOCRINOLOGICAL INVESTIGATION, vol 39, issue 6, pp 715-716
- 2016
-
In: Journal of Endocrinological Investigation. - : SPRINGER. - 0391-4097 .- 1720-8386. ; 39:6, s. 715-716
-
Journal article (other academic/artistic)abstract
- Purpose Pheochromocytomas (PCCs) are rare endocrine tumors originating from the adrenal medulla. These tumors display a highly heterogeneous mutation profile, and a substantial part of the causative genetic events remains to be explained. Recent studies have reported presence of the activating BRAF V600E mutation in PCC, suggesting a role for BRAF activation in tumor development. This study sought to further investigate the occurrence of the BRAF V600E mutation in these tumors. Methods A cohort of 110 PCCs was screened for the BRAF V600E mutation using direct Sanger sequencing. Results All cases investigated displayed wild-type sequences at nucleotide 1799 in the BRAF gene. Conclusions Taken together with all previously screened tumors up to date, only 1 BRAF V600E mutation has been found among 361 PCCs. These findings imply that the BRAF V600E mutation is a rare event in pheochromocytoma.
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| 35. |
- Paulsson, Johan O., et al.
(author)
-
Whole-genome Sequencing of Follicular Thyroid Carcinomas Reveal Recurrent Mutations in MicroRNA Processing Subunit DGCR8
- 2021
-
In: Journal of Clinical Endocrinology and Metabolism. - : Endocrine Society. - 0021-972X .- 1945-7197. ; 106:11, s. 3265-3282
-
Journal article (peer-reviewed)abstract
- Background: The genomic and transcriptomic landscape of widely invasive follicular thyroid carcinomas (wiFTCs) and Hurthle cell carcinoma (HCC) are poorly characterized, and subsets of these tumors lack information on genetic driver events.Objective: The aim of this study was to bridge this gap.Methods: We performed whole-genome and RNA sequencing and subsequent bioinformatic analyses of 11 wiFTCs and 2 HCCs with a particularly poor prognosis, and matched normal tissue.Results: All wiFTCs exhibited one or several mutations in established thyroid cancer genes, including TERT (n=4), NRAS (n=3), HRAS, KRAS, AKT, PTEN, PIK3CA, MUTYH, TSHR, and MEN1 (n=1 each). MutSig2CV analysis revealed recurrent somatic mutations in FAM72D (n=3, in 2 wiFTCs and in a single HCC), TP53 (n=3, in 2 wiFTCs and a single HCC), and EIF1AX (n=3), with DGCR8 (n=2) as borderline significant. The DGCR8 mutations were recurrent p.E518K missense alterations, known to cause familial multinodular goiter via disruption of microRNA (miRNA) processing. Expression analyses showed reduced DGCR8 messenger RNA expression in FTCs in general, and the 2 DGCR8 mutants displayed a distinct miRNA profile compared to DGCR8 wild-types. Copy number analyses revealed recurrent gains on chromosomes 4, 6, and 10, and fusion gene analyses revealed 27 high-quality events. Both HCCs displayed hyperploidy, which was fairly unusual in the FTC cohort. Based on the transcriptome data, tumors amassed in 2 principal clusters.Conclusion: We describe the genomic and transcriptomic landscape in wiFTCs and HCCs and identify novel recurrent mutations and copy number alterations with possible driver properties and lay the foundation for future studies.
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| 36. |
- Paulsson, Johan O., et al.
(author)
-
Whole‐genome sequencing of synchronous thyroid carcinomas identifies aberrant DNA repair in thyroid cancer dedifferentiation
- 2020
-
In: Journal of Pathology. - : Wiley. - 0022-3417 .- 1096-9896. ; 250:2, s. 183-194
-
Journal article (peer-reviewed)abstract
- The genetics underlying thyroid cancer dedifferentiation is only partly understood and has not yet been characterised using comprehensive pan‐genomic analyses. We investigated a unique case with synchronous follicular thyroid carcinoma (FTC), poorly differentiated thyroid carcinoma (PDTC), and anaplastic thyroid carcinoma (ATC), as well as regional lymph node metastases from the PDTC and ATC from a single patient using whole‐genome sequencing (WGS). The FTC displayed mutations in CALR, RB1, and MSH2, and the PDTC exhibited mutations in TP53, DROSHA, APC, TERT, and additional DNA repair genes – associated with an immense increase in sub‐clonal somatic mutations. All components displayed an overrepresentation of C>T transitions with associated microsatellite instability (MSI) in the PDTC and ATC, with borderline MSI in the FTC. Clonality analyses pinpointed a shared ancestral clone enriched for mutations in TP53‐associated regulation of DNA repair and identified important sub‐clones for each tumour component already present in the corresponding preceding lesion. This genomic characterisation of the natural progression of thyroid cancer reveals several novel genes of interest for future studies. Moreover, the findings support the theory of a stepwise dedifferentiation process and suggest that defects in DNA repair could play an important role in the clonal evolution of thyroid cancer.
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| 37. |
- Paulsson, Johan, et al.
(author)
-
The processive kinetics of gene conversion in bacteria
- 2017
-
In: Molecular Microbiology. - : John Wiley & Sons. - 0950-382X .- 1365-2958. ; 104:5, s. 752-760
-
Journal article (peer-reviewed)abstract
- Gene conversion, non-reciprocal transfer from one homologous sequence to another, is a major force in evolutionary dynamics, promoting co-evolution in gene families and maintaining similarities between repeated genes. However, the properties of the transfer - where it initiates, how far it proceeds and how the resulting conversion tracts are affected by mismatch repair - are not well understood. Here, we use the duplicate tuf genes in Salmonella as a quantitatively tractable model system for gene conversion. We selected for conversion in multiple different positions of tuf, and examined the resulting distributions of conversion tracts in mismatch repair-deficient and mismatch repair-proficient strains. A simple stochastic model accounting for the essential steps of conversion showed excellent agreement with the data for all selection points using the same value of the conversion processivity, which is the only kinetic parameter of the model. The analysis suggests that gene conversion effectively initiates uniformly at any position within a tuf gene, and proceeds with an effectively uniform conversion processivity in either direction limited by the bounds of the gene.
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| 38. |
- Paulsson, Johan
(author)
-
The stochastic nature of intracellular control circuits
- 2000
-
Doctoral thesis (other academic/artistic)abstract
- Chemical reactions are probabilistic by nature, causing random fluctuations inconcentrations to emerge spontaneously. In conventional (macroscopic) kinetics this internal noise is ignored under the assumption that average copy numbers are so high that fluctuations are negligible in comparison. By contrast, intracellular regulatory circuits often operate on components present in a few to a few hundred copies. In close analogy with the critical phenomena studied in statistical physics, many metabolic and genetic pathways are also kinetically designed in ways that inevitably generate random ultravariation. Macroscopic kinetics is then not only unsuitable because averages take asubordinate position to fluctuations, but also because it does not accurately account for averages when reaction rates depend nonlinearly on noisy concentrations. In such cases it is necessary to take a stochastic molecular-level (mesoscopic) approach to kinetics where rate equations are replaced by birth and death master equations.This thesis is mainly a master equation analysis of internal noise in intracellular processes. By connecting Biochemical Systems Theory to stochastic kinetics, it is shown how basic principles of metabolic and genetic control circuits, such as sensitivity, robustness and homeostasis, all directly relate to the significance of internal noise. The commonly held notion that signal noise invokes an increased response noise is shown to be based on a linear perspective on fluctuations. Since regulation is generally nonlinear, signal noise may also affect the sensitivity with which reactionrates respond to changes in the average signal concentration. Insensitive regulatory mechanisms can in fact exploit the signal noise that arises from biochemical reactions for increased sensitivity: Stochastic Focusing. In regulatory circuits this may result in `kinetic uncertainty principles' where the uncertainty in one component can be decreased only by increasing the uncertainty in another component.The origins and effects of internal noise are mainly exemplified here by copynumber control of plasmids Co1E1 and R1. Plasmids are simple, well-characterized systems and subject to a strong selective pressure to reduce both copy number averages and fluctuations, making them ideal for mesoscopic modeling.
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| 39. |
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| 40. |
- Paulsson, Magnus, et al.
(author)
-
Bacterial Outer Membrane Vesicles Induce Vitronectin Release Into the Bronchoalveolar Space Conferring Protection From Complement-Mediated Killing
- 2018
-
In: Frontiers in Microbiology. - : Frontiers Media SA. - 1664-302X. ; 9
-
Journal article (peer-reviewed)abstract
- Pathogens causing pneumonia utilize the complement regulator vitronectin to evade complement-mediated killing. Although vitronectin is associated with several chronic lung diseases, the role of bronchoalveolar vitronectin in pneumonia has not been studied. This study sought to reveal the involvement of vitronectin in the bronchoalveolar space during pneumonia, to assess the effect of outer membrane vesicles and endotoxin on vitronectin release, and to determine whether bacterial pathogens utilize pulmonary vitronectin for evasion. Vitronectin was analyzed in cell-free bronchoalveolar lavage fluid harvested from patients with pneumonia (n = 8) and from healthy volunteers after subsegmental endotoxin instillation (n = 13). Vitronectin binding by Pseudomonas aeruginosa and Haemophilus influenzae was analyzed, and subsequent complement evasion was assessed by serum challenge. The effects of outer membrane vesicles on vitronectin production in mouse lungs and human type II alveolar epithelial cells (A549) were determined. We detected increased vitronectin concentrations in lavage fluid during pneumonia (p = 0.0063) and after bronchial endotoxin challenge (p = 0.016). The capture of vitronectin by bacteria significantly reduced complement-mediated lysis. Following challenge with vesicles, vitronectin was detected in mouse bronchoalveolar space, and mouse alveolar epithelial cells in vivo as well as A549 cells in vitro contained increased levels of vitronectin. Taken together, outer membrane vesicles and endotoxin from Gram-negative bacteria induce vitronectin, which is released into the bronchoalveolar space, and used for evasion of complement-mediated clearance.
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| 41. |
- Paulsson-Tralla, J., et al.
(author)
-
Estimation of chloride ingress in uncracked and cracked concrete using measured surface concentrations
- 2002
-
In: ACI Materials Journal. - 0889-325X .- 1944-737X. ; 99:1, s. 27-36
-
Journal article (peer-reviewed)abstract
- The service life of repaired concrete bridge decks with chloride-initiated corrosion is estimated using real environmental loads. Major field data are presented from measurements of the surface concentration (SC) of chloride ions in concrete overlays in deicing environments. The diffusion coefficients (DC) of the overlay and the old concrete were estimated with different methods, used thereafter with the measured SC and the measured concrete covers (lower 5% percentile), to predict the service life with numerical methods. Numerical methods were used due to the varying SC, and because the concrete overlay and the old concrete bridge deck had different DC, and because the composite deck could hardly be treated as a semi-infinite body. The effect of chloride ions that accumulated at the soffit had to be considered for thin bridge decks. Both uncracked and cracked concrete were considered. The effect of the SC type on the service life was limited. Stopping the use of deicing agents was found to be beneficial for up to 30 to 40 years. Cracks increased the chloride ingress rate, and the effect increased considerably with high DC in the old concrete.
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| 42. |
- Ravi, Naveen, et al.
(author)
-
Global RNA expression and DNA methylation patterns in primary anaplastic thyroid cancer
- 2020
-
In: Cancers. - : MDPI AG. - 2072-6694. ; 12:3
-
Journal article (peer-reviewed)abstract
- Anaplastic thyroid cancer (ATC) is one of the most malignant tumors, with a median survival of only a few months. The tumorigenic processes of this disease have not yet been completely unraveled. Here, we report an mRNA expression and DNA methylation analysis of fourteen primary ATCs. ATCs clustered separately from normal thyroid tissue in unsupervised analyses, both by RNA expression and by DNA methylation. In expression analysis, enrichment of cell-cycle-related genes as well as downregulation of genes related to thyroid function were seen. Furthermore, ATC displayed a global hypomethylation of the genome but with hypermethylation of CpG islands. Notably, several cancer-related genes displayed a correlation between RNA expression and DNA methylation status, including MTOR, NOTCH1, and MAGI1. Furthermore, TSHR and SLC26A7, encoding the thyroid-stimulating hormone receptor and an iodine receptor highly expressed in normal thyroid, respectively, displayed low expression as well as aberrant gene body DNA methylation. This study is the largest investigation of global DNA methylation in ATC to date. It shows that aberrant DNA methylation is common in ATC and likely contributes to tumorigenesis in this disease. Future explorations of novel treatments should take this into consideration.
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| 43. |
- Ravi, Naveen, et al.
(author)
-
Identification of targetable lesions in anaplastic thyroid cancer by genome profiling
- 2019
-
In: Cancers. - : MDPI AG. - 2072-6694. ; 11:3
-
Journal article (peer-reviewed)abstract
- Anaplastic thyroid cancer (ATC) is a rare and extremely malignant tumor with no available cure. The genetic landscape of this malignancy has not yet been fully explored. In this study, we performed whole exome sequencing and the RNA-sequencing of fourteen cases of ATC to delineate copy number changes, fusion gene events, and somatic mutations. A high frequency of genomic amplifications was seen, including 29% of cases having amplification of CCNE1 and 9% of CDK6; these events may be targetable by cyclin dependent kinase (CDK) inhibition. Furthermore, 9% harbored amplification of TWIST1, which is also a potentially targetable lesion. A total of 21 fusion genes in five cases were seen, none of which were recurrent. Frequent mutations included TP53 (55%), the TERT promoter (36%), and ATM (27%). Analyses of mutational signatures showed an involvement of processes that are associated with normal aging, defective DNA mismatch repair, activation induced cytidine deaminase (AID)/apolipoprotein B editing complex (APOBEC) activity, failure of DNA double-strand break repair, and tobacco exposure. Taken together, our results shed new light on the tumorigenesis of ATC and show that a relatively large proportion (36%) of ATCs harbor genetic events that make them candidates for novel therapeutic approaches. When considering that ATC today has a mortality rate of close to 100%, this is highly relevant from a clinical perspective.
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| 44. |
- Reuveni, Shlomi, et al.
(author)
-
Ribosomes are optimized for autocatalytic production
- 2017
-
In: Nature. - : NATURE PUBLISHING GROUP. - 0028-0836 .- 1476-4687. ; 547:7663, s. 293-297
-
Journal article (peer-reviewed)abstract
- Many fine-scale features of ribosomes have been explained in terms of function, revealing a molecular machine that is optimized for error-correction, speed and control. Here we demonstrate mathematically that many less well understood, larger-scale features of ribosomes-such as why a few ribosomal RNA molecules dominate the mass and why the ribosomal protein content is divided into 55-80 small, similarly sized segments-speed up their autocatalytic production.
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| 45. |
- Saito, Roy-Akira, et al.
(author)
-
Forkhead box F1 regulates tumor-promoting properties of cancer-associated fibroblasts in lung cancer.
- 2010
-
In: Cancer research. - 1538-7445 .- 0008-5472. ; 70:7, s. 2644-54
-
Journal article (peer-reviewed)abstract
- Cancer-associated fibroblasts (CAF) attract increasing attention as potential cancer drug targets due to their ability to stimulate, for example, tumor growth, invasion, angiogenesis, and metastasis. However, the molecular mechanisms causing the tumor-promoting properties of CAFs remain poorly understood. Forkhead box F1 (FoxF1) is a mesenchymal target of hedgehog signaling, known to regulate mesenchymal-epithelial interactions during lung development. Studies with FoxF1 gain- and loss-of-function fibroblasts revealed that FoxF1 regulates the contractility of fibroblasts, their production of hepatocyte growth factor and fibroblast growth factor-2, and their stimulation of lung cancer cell migration. FoxF1 status of fibroblasts was also shown to control the ability of fibroblasts to stimulate xenografted tumor growth. FoxF1 was expressed in CAFs of human lung cancer and associated with activation of hedgehog signaling. These observations suggest that hedgehog-dependent FoxF1 is a clinically relevant lung CAF-inducing factor, and support experimentally the general concept that CAF properties can be induced by activation of developmentally important transcription factors.
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| 46. |
- Sauma, Lilian, et al.
(author)
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Peroxisome proliferator activated receptor gamma activity is low in mature primary human visceral adipocytes
- 2007
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In: Diabetologia. - : Springer Science and Business Media LLC. - 0012-186X .- 1432-0428. ; 50:1, s. 195-201
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Journal article (peer-reviewed)abstract
- AIMS/HYPOTHESIS: The amount of visceral fat mass strongly relates to insulin resistance in humans. The transcription factor peroxisome proliferator activated receptor gamma (PPARG) is abundant in adipocytes and regulates genes of importance for insulin sensitivity. Our objective was to study PPARG activity in human visceral and subcutaneous adipocytes and to compare this with the most common model for human disease, the mouse.MATERIALS AND METHODS: We transfected primary human adipocytes with a plasmid encoding firefly luciferase controlled by PPARG response element (PPRE) from the acyl-CoA-oxidase gene and measured PPRE activity by emission of light. RESULTS: We found that PPRE activity was 6.6-fold higher (median) in adipocytes from subcutaneous than from omental fat from the same subjects (n = 23). The activity was also 6.2-fold higher in subcutaneous than in intra-abdominal fat cells when we used a PPARG ligand-binding domain-GAL4 fusion protein as reporter, demonstrating that the difference in PPRE activity was due to different levels of activity of the PPARG receptor in the two fat depots. Stimulation with 5 micromol/l rosiglitazone did not induce a PPRE activity in visceral adipocytes that was as high as basal levels in subcutaneous adipocytes. Interestingly, in mice of two different strains the PPRE activity was similar in visceral and subcutaneous fat cells.CONCLUSIONS/INTERPRETATION: We found considerably lower PPARG activity in visceral than in subcutaneous primary human adipocytes. Further studies of the molecular mechanisms behind this difference could lead to development of drugs that target the adverse effects of visceral obesity.
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| 47. |
- Stenman, Adam, et al.
(author)
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Pan-genomic characterization of high-risk pediatric papillary thyroid carcinoma
- 2021
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In: Endocrine-Related Cancer. - 1351-0088 .- 1479-6821. ; 28:5, s. 337-351
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Journal article (peer-reviewed)abstract
- Pediatric papillary thyroid carcinomas (pPTCs) are often indolent tumors with excellent long- term outcome, although subsets of cases are clinically troublesome and recur. Although it is generally thought to exhibit similar molecular aberrancies as their counterpart tumors in adults, the pan-genomic landscape of clinically aggressive pPTCs has not been previously described. In this study, five pairs of primary and synchronously metastatic pPTC from patients with high-risk phenotypes were characterized using parallel whole-genome and -transcriptome sequencing. Primary tumors and their metastatic components displayed an exceedingly low number of coding somatic mutations and gross chromosomal alterations overall, with surprisingly few shared mutational events. Two cases exhibited one established gene fusion event each (SQSTM1-NTRK3 and NCOA4-RET) in both primary and metastatic tissues, and one case each was positive for a BRAF V600E mutation and a germline truncating CHEK2 mutation, respectively. One single case was without apparent driver events and was considered as a genetic orphan. Non-coding mutations in cancer-associated regions were generally not present. By expressional analyses, fusion-driven primary and metastatic pPTC clustered separately from the mutation-driven cases and the sole genetic orphan. We conclude that pPTCs are genetically indolent tumors with exceedingly stable genomes. Several mutations found exclusively in the metastatic samples which may represent novel genetic events that drive the metastatic behavior, and the differences in mutational compositions suggest early clonal divergence between primary tumors and metastases. Moreover, an overrepresentation of mutational and expressional dysregulation of immune regulatory pathways was noted among fusion-positive pPTC metastases, suggesting that these tumors might facilitate spread through immune evasive mechanisms.
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| 48. |
- Wallsten, Anna, 1980-, et al.
(author)
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Statlig styrförmåga i framtider med smart mobilitet
- 2019
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Reports (other academic/artistic)abstract
- Studien syftar till att öka kunskapen om hur statens förmåga att styra mot transportpolitiska mål kan förändras i olika framtider med smart mobilitet. Smart mobilitet kan förstås som ett paraplybegrepp som samlar ett antal olika trender inom transportsektorn och som alla har det gemensamt att de knyter an till digitalisering. Generellt handlar omställningen mot smart mobilitet om två parallella processer: dels en utveckling i riktning mot självkörande och uppkopplade fordon, dels en utveckling i riktning mot nya former av delad mobilitet.Analysen har baserats på det svenska transportsystemet men vi bedömer det som troligt att analyserna på en aggregerad nivå kommer vara giltig även i andra länder med liknande transportsystem. Vi konstaterar att staten idag förfogar över en stor mängd styrmedel, och sannolikt kommer många av dagens styrmedel vara aktuella även i en framtid med smart mobilitet. Vissa styrmedel påverkas direkt av smart mobilitet. Primärt styrmedel som drar nytta av uppkopplade fordon. Statens möjligheter är avhängigt deras tillgång till data och syn på sin egen roll att styra transportsystemet. Smart mobilitet kan även mer indirekt påverka styrningskapaciteten för olika styrmedel. Det beror på olika antaganden om trafikens utveckling, exempelvis ökad biltrafik eller mer delad mobilitet. Frågor om samhällets organisation har också stor betydelse. Smart mobilitet aktualiserar t.ex. att staten behöver ha en annan kompetens för att effektivt kunna verka i framtiden.
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| 49. |
- Wayne, Greg, et al.
(author)
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Principles of Systems Biology, No. 11
- 2016
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In: CELL SYSTEMS. - : CELL PRESS. - 2405-4712. ; 3:5, s. 406-410
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Journal article (peer-reviewed)abstract
- This month: AI that learns patterns and facts, new protein-RNA and protein-protein relationships, engineering signaling and metabolism, and more variants of Cas9.
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| 50. |
- Wiberg, Johan, 1977-
(author)
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Bridge Monitoring to Allow for Reliable Dynamic FE Modelling : A Case Study of the New Årsta Railway Bridge
- 2006
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Licentiate thesis (other academic/artistic)abstract
- Today’s bridge design work in many cases demands a trustworthy dynamic analysis instead of using the traditional dynamic amplification factors. In this thesis a reliable 3D Bernoulli-Euler beam finite element model of the New Årsta Railway Bridge was prepared for thorough dynamic analysis using in situ bridge monitoring for correlation. The bridge is of the concrete box girder type with a heavily reinforced and prestressed bridge deck. The monitoring system was designed for long term monitoring with strain transducers embedded in the concrete and accelerometers mounted inside the edge beams and at the lower edge of the track slab. The global finite element model used the exact bridge geometry but was simplified regarding prestressing cables and the two railway tracks. The prestressing cables and the tracks were consequently not included and an equivalent pure concrete model was identified. A static macadam train load was eccentrically placed on one of the bridge’s two tracks. By using Vlasov’s torsional theory and thereby including constrained warping a realistic modulus of elasticity for the concrete without prestressing cables and stiffness contribution from the railway tracks was found. This was allowed by comparing measured strain from strain transducers with the linear elastic finite element model’s axial stresses. Mainly three monitoring bridge sections were used, each of which was modelled with plane strain finite elements subjected to sectional forces/moments from a static macadam train load and a separately calculated torsional curvature. From the identified modulus of elasticity the global finite element model was updated for Poisson’s ratio and material density (mass) to correspond with natural frequencies from the performed signal analysis of accelerometer signals. The influence of warping on the natural frequencies of the global finite element model was assumed small and the bridge’s torsional behaviour was modelled to follow Saint-Venant’s torsional theory. A first preliminary estimation of modal damping ratios was included. The results indicated that natural frequencies were in accordance between modelling and signal analysis results, especially concerning high energy modes. Estimated damping ratios for the first vibration modes far exceeded the lower limit value specified in bridge design codes and railway bridge dynamic analysis recommendations.
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