| 1. |
|
|
| 2. |
|
|
| 3. |
- Almlöf, Jonas Carlsson, et al.
(author)
-
Powerful Identification of Cis-regulatory SNPs in Human Primary Monocytes Using Allele-Specific Gene Expression
- 2012
-
In: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 7:12, s. e52260-
-
Journal article (peer-reviewed)abstract
- A large number of genome-wide association studies have been performed during the past five years to identify associations between SNPs and human complex diseases and traits. The assignment of a functional role for the identified disease-associated SNP is not straight-forward. Genome-wide expression quantitative trait locus (eQTL) analysis is frequently used as the initial step to define a function while allele-specific gene expression (ASE) analysis has not yet gained a wide-spread use in disease mapping studies. We compared the power to identify cis-acting regulatory SNPs (cis-rSNPs) by genome-wide allele-specific gene expression (ASE) analysis with that of traditional expression quantitative trait locus (eQTL) mapping. Our study included 395 healthy blood donors for whom global gene expression profiles in circulating monocytes were determined by Illumina BeadArrays. ASE was assessed in a subset of these monocytes from 188 donors by quantitative genotyping of mRNA using a genome-wide panel of SNP markers. The performance of the two methods for detecting cis-rSNPs was evaluated by comparing associations between SNP genotypes and gene expression levels in sample sets of varying size. We found that up to 8-fold more samples are required for eQTL mapping to reach the same statistical power as that obtained by ASE analysis for the same rSNPs. The performance of ASE is insensitive to SNPs with low minor allele frequencies and detects a larger number of significantly associated rSNPs using the same sample size as eQTL mapping. An unequivocal conclusion from our comparison is that ASE analysis is more sensitive for detecting cis-rSNPs than standard eQTL mapping. Our study shows the potential of ASE mapping in tissue samples and primary cells which are difficult to obtain in large numbers.
|
|
| 4. |
|
|
| 5. |
- Cortese, Katia, et al.
(author)
-
The HSP90 inhibitor geldanamycin perturbs endosomal structure and drives recycling ErbB2 and transferrin to modified MVBs/lysosomal compartments
- 2013
-
In: Molecular Biology of the Cell. - : The American Society for Cell Biology. - 1059-1524 .- 1939-4586. ; 24:2, s. 129-144
-
Journal article (peer-reviewed)abstract
- The ErbB2 receptor is a clinically validated cancer target whose internalization and trafficking mechanisms remain poorly understood. HSP90 inhibitors, such as geldanamycin (GA), have been developed to target the receptor to degradation or to modulate downstream signaling. Despite intense investigations, the entry route and postendocytic sorting of ErbB2 upon GA stimulation have remained controversial. We report that ErbB2 levels inversely impact cell clathrin-mediated endocytosis (CME) capacity. Indeed, the high levels of the receptor are responsible for its own low internalization rate. GA treatment does not directly modulate ErbB2 CME rate but it affects ErbB2 recycling fate, routing the receptor to modified multivesicular endosomes (MVBs) and lysosomal compartments, by perturbing early/recycling endosome structure and sorting capacity. This activity occurs irrespective of the cargo interaction with HSP90, as both ErbB2 and the constitutively recycled, HSP90-independent, transferrin receptor are found within modified endosomes, and within aberrant, elongated recycling tubules, leading to modified MVBs/lysosomes. We propose that GA, as part of its anticancer activity, perturbs early/recycling endosome sorting, routing recycling cargoes toward mixed endosomal compartments.
|
|
| 6. |
- Doherty, Gary J., et al.
(author)
-
The endocytic protein GRAF1 is directed to cell-matrix adhesion sites and regulates cell spreading
- 2011
-
In: Molecular Biology of the Cell. - Bethesda : American Society for Cell Biology. - 1059-1524 .- 1939-4586. ; 22:22, s. 4380-4389
-
Journal article (peer-reviewed)abstract
- The rho GTPase-activating protein GTPase regulator associated with focal adhesion kinase-1 (GRAF1) remodels membranes into tubulovesicular clathrin-independent carriers (CLICs) mediating lipid-anchored receptor endocytosis. However, the cell biological functions of this highly prevalent endocytic pathway are unclear. In this article, we present biochemical and cell biological evidence that GRAF1 interacted with a network of endocytic and adhesion proteins and was found enriched at podosome-like adhesions and src-induced podosomes. We further demonstrate that these sites comprise microdomains of highly ordered lipid enriched in GRAF1 endocytic cargo. GRAF1 activity was upregulated in spreading cells and uptake via CLICs was concentrated at the leading edge of migrating cells. Depletion of GRAF1, which inhibits CLIC generation, resulted in profound defects in cell spreading and migration. We propose that GRAF1 remodels membrane microdomains at adhesion sites into endocytic carriers, facilitating membrane turnover during cell morphological changes.
|
|
| 7. |
- Eberth, Alexander, et al.
(author)
-
A BAR domain-mediated autoinhibitory mechanism for RhoGAPs of the GRAF family
- 2009
-
In: Biochemical Journal. - 0264-6021 .- 1470-8728. ; 417:1, s. 371-377
-
Journal article (peer-reviewed)abstract
- The BAR (Bin/amphiphysin/Rvs) domain defines an emerging superfamily of proteins implicated in fundamental biological processes by sensing and inducing membrane curvature. We identified a novel autoregulatory function for the BAR domain of two related GAPs' (GTPase-activating proteins) of the GRAF (GTPase regulator associated with focal adhesion kinase) subfamily. We demonstrate that the N-terminal fragment of these GAPs including the BAR domain interacts directly with the GAP domain and inhibits its activity. Analysis of various BAR and GAP domains revealed that the BAR domain-mediated inhibition of these GAPs' function is highly specific. These GAPs, in their autoinhibited state, are able to bind and tubulate liposomes in vitro, and to generate lipid tubules in cells. Taken together, we identified BAR domains as cis-acting inhibitory elements that very likely mask the active sites of the GAP domains and thus prevent down-regulation of Rho proteins. Most remarkably, these BAR proteins represent a dual-site system with separate membrane-tubulation and GAP-inhibitory functions that operate simultaneously.
|
|
| 8. |
- Hyvonen, R., et al.
(author)
-
The likely impact of elevated [CO2], nitrogen deposition, increased temperature and management on carbon sequestration in temperate and boreal forest ecosystems: a literature review
- 2007
-
In: New Phytologist. - Cambridge : Wiley. - 0028-646X .- 1469-8137. ; 173:3, s. 463-480
-
Research review (peer-reviewed)abstract
- Temperate and boreal forest ecosystems contain a large part of the carbon stored on land, in the form of both biomass and soil organic matter. Increasing atmospheric [CO2], increasing temperature, elevated nitrogen deposition and intensified management will change this C store. Well documented single-factor responses of net primary production are: higher photosynthetic rate (the main [CO2] response); increasing length of growing season (the main temperature response); and higher leaf-area index (the main N deposition and partly [CO2] response). Soil organic matter will increase with increasing litter input, although priming may decrease the soil C stock initially, but litter quality effects should be minimal (response to [CO2], N deposition, and temperature); will decrease because of increasing temperature; and will increase because of retardation of decomposition with N deposition, although the rate of decomposition of high-quality litter can be increased and that of low-quality litter decreased. Single-factor responses can be misleading because of interactions between factors, in particular those between N and other factors, and indirect effects such as increased N availability from temperature-induced decomposition. In the long term the strength of feedbacks, for example the increasing demand for N from increased growth, will dominate over short-term responses to single factors. However, management has considerable potential for controlling the C store.
|
|
| 9. |
- Lundmark, A., et al.
(author)
-
Gene expression profiling of periodontitis-affected gingival tissue by spatial transcriptomics
- 2018
-
In: Scientific Reports. - : Nature Publishing Group. - 2045-2322. ; 8:1
-
Journal article (peer-reviewed)abstract
- Periodontitis is a highly prevalent chronic inflammatory disease of the periodontium, leading ultimately to tooth loss. In order to characterize the gene expression of periodontitis-affected gingival tissue, we have here simultaneously quantified and localized gene expression in periodontal tissue using spatial transcriptomics, combining RNA sequencing with histological analysis. Our analyses revealed distinct clusters of gene expression, which were identified to correspond to epithelium, inflamed areas of connective tissue, and non-inflamed areas of connective tissue. Moreover, 92 genes were identified as significantly up-regulated in inflamed areas of the gingival connective tissue compared to non-inflamed tissue. Among these, immunoglobulin lambda-like polypeptide 5 (IGLL5), signal sequence receptor subunit 4 (SSR4), marginal zone B and B1 cell specific protein (MZB1), and X-box binding protein 1 (XBP1) were the four most highly up-regulated genes. These genes were also verified as significantly higher expressed in gingival tissue of patients with periodontitis compared to healthy controls, using reverse transcription quantitative polymerase chain reaction. Moreover, the protein expressions of up-regulated genes were verified in gingival biopsies by immunohistochemistry. In summary, in this study, we report distinct gene expression signatures within periodontitis-affected gingival tissue, as well as specific genes that are up-regulated in inflamed areas compared to non-inflamed areas of gingival tissue. The results obtained from this study may add novel information on the genes and cell types contributing to pathogenesis of the chronic inflammatory disease periodontitis.
|
|
| 10. |
- Lundmark, Richard, et al.
(author)
-
The GTPase-activating protein GRAF1 regulates the CLIC/GEEC endocytic pathway
- 2008
-
In: Current Biology. - : Elsevier BV. - 0960-9822 .- 1879-0445. ; 18:22, s. 1802-1808
-
Journal article (peer-reviewed)abstract
- Clathrin-independent endocytosis is an umbrella term for a variety of endocytic pathways that internalize numerous cargoes independently of the canonical coat protein Clathrin [1, 2]. Electron-microscopy studies have defined the pleiomorphic CLathrin-Independent Carriers (CLICs) and GPI-Enriched Endocytic Compartments (GEECs) as related major players in such uptake [3, 4]. This CLIC/GEEC pathway relies upon cellular signaling and activation through small G proteins, but mechanistic insight into the biogenesis of its tubular and tubulovesicular carriers is lacking. Here we show that the Rho-GAP-domain-containing protein GRAF1 marks, and is indispensable for, a major Clathrin-independent endocytic pathway. This pathway is characterized by its ability to internalize bacterial exotoxins, GPI-linked proteins, and extracellular fluid. We show that GRAF1 localizes to PtdIns(4,5)P2-enriched, tubular, and punctate lipid structures via N-terminal BAR and PH domains. These membrane carriers are relatively devoid of caveolin1 and flotillin1 but are associated with activity of the small G protein Cdc42. This study provides the first specific noncargo marker for CLIC/GEEC endocytic membranes and demonstrates how GRAF1 can coordinate small G protein signaling and membrane remodeling to facilitate internalization of CLIC/GEEC pathway cargoes.
|
|
| 11. |
- Morén, Björn, et al.
(author)
-
EHD2 regulates caveolar dynamics via ATP-driven targeting and oligomerization
- 2012
-
In: Molecular Biology of the Cell. - : American society for cell biology. - 1059-1524 .- 1939-4586. ; 23:7, s. 1316-1329
-
Journal article (peer-reviewed)abstract
- Eps15 homology domain-containing 2 (EHD2) belongs to the EHD-containing protein family of dynamin-related ATPases involved in membrane remodeling in the endosomal system. EHD2 dimers oligomerize into rings on highly curved membranes, resulting in stimulation of the intrinsic ATPase activity. In this paper, we report that EHD2 is specifically and stably associated with caveolae at the plasma membrane and not involved in clathrin-mediated endocytosis or endosomal recycling, as previously suggested. EHD2 interacts with pacsin2 and cavin1, and ordered membrane assembly of EHD2 is dependent on cavin1 and caveolar integrity. While the EHD of EHD2 is dispensable for targeting, we identified a loop in the nucleotide-binding domain that, together with ATP binding, is required for caveolar localization. EHD2 was not essential for the formation or shaping of caveolae, but high levels of EHD2 caused distortion and loss of endogenous caveolae. Assembly of EHD2 stabilized and constrained caveolae to the plasma membrane to control turnover, and depletion of EHD2, resulting in endocytic and more dynamic and short-lived caveolae. Thus, following the identification of caveolin and cavins, EHD2 constitutes a third structural component of caveolae involved in controlling the stability and turnover of this organelle.
|
|
| 12. |
- Thelaus, J., et al.
(author)
-
Francisella tularensis Subspecies holarctica Occurs in Swedish Mosquitoes, Persists Through the Developmental Stages of Laboratory-Infected Mosquitoes and Is Transmissible During Blood Feeding
- 2014
-
In: Microbial Ecology. - : Springer Science and Business Media LLC. - 0095-3628 .- 1432-184X. ; 67:1, s. 96-107
-
Journal article (peer-reviewed)abstract
- In Sweden, mosquitoes are considered the major vectors of the bacterium Francisella tularensis subsp. holarctica, which causes tularaemia. The aim of this study was to investigate whether mosquitoes acquire the bacterium as aquatic larvae and transmit the disease as adults. Mosquitoes sampled in a Swedish area where tularaemia is endemic (A-rebro) were positive for the presence of F. tularensis deoxyribonucleic acid throughout the summer. Presence of the clinically relevant F. tularensis subsp. holarctica was confirmed in 11 out of the 14 mosquito species sampled. Experiments performed using laboratory-reared Aedes aegypti confirmed that F. tularensis subsp. holarctica was transstadially maintained from orally infected larvae to adult mosquitoes and that 25 % of the adults exposed as larvae were positive for the presence of F. tularensis-specific sequences for at least 2 weeks. In addition, we found that F. tularensis subsp. holarctica was transmitted to 58 % of the adult mosquitoes feeding on diseased mice. In a small-scale in vivo transmission experiment with F. tularensis subsp. holarctica-positive adult mosquitoes and susceptible mice, none of the animals developed tularaemia. However, we confirmed that there was transmission of the bacterium to blood vials by mosquitoes that had been exposed to the bacterium in the larval stage. Taken together, these results provide evidence that mosquitoes play a role in disease transmission in part of Sweden where tularaemia recurs.
|
|
| 13. |
- Alim, MA, et al.
(author)
-
Pleckstrin Levels Are Increased in Patients with Chronic Periodontitis and Regulated via the MAP Kinase-p38α Signaling Pathway in Gingival Fibroblasts
- 2022
-
In: Frontiers in immunology. - : Frontiers Media SA. - 1664-3224. ; 12, s. 801096-
-
Journal article (peer-reviewed)abstract
- Chronic periodontitis (CP) is a bacteria-driven inflammatory disease characterized by the breakdown of gingival tissue, the periodontal ligament, and alveolar bone, leading ultimately to tooth loss. We previously reported the pleckstrin gene (PLEK) to be highly upregulated in gingival tissue of patients with CP and the only gene concurrently upregulated in other inflammatory diseases including rheumatoid arthritis and cardiovascular diseases. Using saliva from 169 individuals diagnosed with CP and healthy controls, we investigated whether pleckstrin could serve as a novel biomarker of periodontitis. Additionally, we explored signal pathways involved in the regulation of PLEK using human gingival fibroblasts (HGFs). Pleckstrin levels were significantly higher (p < 0.001) in the saliva samples of patients with CP compared to controls and closely associated with CP severity. Immunohistochemical analysis revealed the expression of pleckstrin in inflammatory cells and gingival fibroblasts of CP patients. To explore the signal pathways involved in pleckstrin regulation, we stimulated HGFs with either interleukin-1β (IL-1β) or lipopolysaccharides (LPS) alone, or in combination with inhibitors targeting c-Jun N-terminal kinase, tyrosine kinase, protein kinase C, or p38 MAP kinase. Results showed that IL-1β and LPS significantly increased PLEK mRNA and pleckstrin protein levels. VX-745, the p38 MAP kinase inhibitor significantly decreased IL-1β- and LPS-induced pleckstrin levels at both the mRNA and the protein level. Together, these findings show that pleckstrin could serve as a salivary biomarker for the chronic inflammatory disease periodontitis and a regulator of inflammation via the p38 MAP kinase pathway.
|
|
| 14. |
|
|
| 15. |
- Brandsten, C, et al.
(author)
-
Expression of collagen alpha1(I) mRNA variants during tooth and bone formation in the rat
- 1999
-
In: Journal of dental research. - : SAGE Publications. - 0022-0345 .- 1544-0591. ; 78:1, s. 11-19
-
Journal article (peer-reviewed)abstract
- Collagen al(I) mRNA is composed of two variants of 5 and 6 kb, differing in the length of the 3' untranslated region. In this work, the nucleotide sequences of the two rat mRNA variants were compared, and their expression pattern in cells forming bone, dentin, and cementum were analyzed. The sequences were determined from cDNA inserts of tooth and bone libraries plus directly from PCR fragments, obtained from bone. A total of 5721 bases of the rat collagen α1(I) sequence from cDNA of tooth and bone was determined. All sequences of the short variant were represented in the long variant. Only the alternatively poly-A additions gave rise to the variants in hard tissue. Two oligonucleotides were chosen as probes, one of which recognized, on Northern blots, the two bands of 5 and 6 kb, and the other the 6-kb variant only. The oligonucleotides were used in in situ hybridization experiments, for study of the distribution of the variants in different extracellular matrix-forming cells. Osteoblasts, odontoblasts, and cementum-associated cells were closely examined in sections from rat maxillae from 2 to 25 days of age. A similar or identical pattern of mRNA expression was observed with both oligonucleotides, indicating that the two mRNA variants were co-expressed in all cases.
|
|
| 16. |
|
|
| 17. |
|
|
| 18. |
- Daumke, Oliver, et al.
(author)
-
Architectural and mechanistic insights into an EHD ATPase involved in membrane remodelling
- 2007
-
In: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 449:7164, s. 923-927
-
Journal article (peer-reviewed)abstract
- The ability to actively remodel membranes in response to nucleotide hydrolysis has largely been attributed to GTPases of the dynamin superfamily, and these have been extensively studied. Eps15 homology (EH)-domain-containing proteins (EHDs/RME-1/pincher) comprise a less-well-characterized class of highly conserved eukaryotic ATPases implicated in clathrin-independent endocytosis, and recycling from endosomes. Here we show that EHDs share many common features with the dynamin superfamily, such as a low affinity for nucleotides, the ability to tubulate liposomes in vitro, oligomerization around lipid tubules in ring-like structures and stimulated nucleotide hydrolysis in response to lipid binding. We present the structure of EHD2, bound to a non-hydrolysable ATP analogue, and provide evidence consistent with a role for EHDs in nucleotide-dependent membrane remodelling in vivo. The nucleotide-binding domain is involved in dimerization, which creates a highly curved membrane-binding region in the dimer. Oligomerization of dimers occurs on another interface of the nucleotide-binding domain, and this allows us to model the EHD oligomer. We discuss the functional implications of the EHD2 structure for understanding membrane deformation.
|
|
| 19. |
- de Lange, Annet H., et al.
(author)
-
Opportunities and challenges in designing and evaluating complex multilevel, multi-stakeholder occupational health interventions in practice
- 2024
-
In: Work & Stress. - : Taylor & Francis. - 0267-8373 .- 1464-5335.
-
Journal article (peer-reviewed)abstract
- Extant research suggests the effectiveness of Occupational Health Psychology (OHP) interventions depends on their design in the broader organisational context. While the field recognises that pre- and posttest evaluation do not sufficiently capture the complex dynamics around OHP interventions, complex multi-level OHP interventions are still scarce in the literature. As established intervention implementation frameworks suggest, it remains difficult to address this complexity in practice. The present position paper re-evaluates lessons learned from two complex European OHP intervention projects, by applying the Integrated Process Evaluation Framework (IPEF) and related theories to bridge the gap between the theoretically recognised complexity and practical challenges. The re-evaluations emphasise that programme-multilevel theories rooted in OHP-perspectives contribute to adequately hypothesising around systemic factors and mechanisms relevant to OHP interventions. Concretely, middle range theories that outline how an intervention’s mechanisms work within a specific context to produce certain outcomes are crucial. Additionally, strategically and actively involving key stakeholders at all levels of the system and across the different intervention phases improves the embedding of OHP interventions in organisations. We elaborate on these insights with seven concrete recommendations for complex OHP intervention research.
|
|
| 20. |
|
|
| 21. |
|
|
| 22. |
- Howes, Mark T, et al.
(author)
-
Clathrin-independent carriers form a high capacity endocytic sorting system at the leading edge of migrating cells
- 2010
-
In: Journal of Cell Biology. - : Rockefeller University Press. - 0021-9525 .- 1540-8140. ; 190:4, s. 675-691
-
Journal article (peer-reviewed)abstract
- Although the importance of clathrin- and caveolin-independent endocytic pathways has recently emerged, key aspects of these routes remain unknown. Using quantitative ultrastructural approaches, we show that clathrin-independent carriers (CLICs) account for approximately three times the volume internalized by the clathrin-mediated endocytic pathway, forming the major pathway involved in uptake of fluid and bulk membrane in fibroblasts. Electron tomographic analysis of the 3D morphology of the earliest carriers shows that they are multidomain organelles that form a complex sorting station as they mature. Proteomic analysis provides direct links between CLICs, cellular adhesion turnover, and migration. Consistent with this, CLIC-mediated endocytosis of key cargo proteins, CD44 and Thy-1, is polarized at the leading edge of migrating fibroblasts, while transient ablation of CLICs impairs their ability to migrate. These studies provide the first quantitative ultrastructural analysis and molecular characterization of the major endocytic pathway in fibroblasts, a pathway that provides rapid membrane turnover at the leading edge of migrating cells.
|
|
| 23. |
|
|
| 24. |
|
|
| 25. |
- Katerelos, D.T.G., et al.
(author)
-
Analysis of matrix cracking in GFRP laminates using Raman spectroscopy
- 2007
-
In: Composites Science And Technology. - : Elsevier BV. - 0266-3538 .- 1879-1050. ; 67:9, s. 1946-1954
-
Journal article (peer-reviewed)abstract
- A Raman spectroscopic technique was used to investigate the elastic modulus degradation and the residual strain development in cross-ply and [0/452/0]T glass fibre/epoxy laminates. Glass has a poor Raman signal and, therefore, embedded aramid fibres were used as strain sensors for mapping of the internal strain development within the 0° ply due to matrix cracking in the off-axis ply. The elastic modulus and the residual strain were derived from the changes of the distance between well identified strain "peaks" on the aramid fibres. The elastic modulus reduction and the residual strain development are described by a closed form model. The modulus reduction predictions are accurate, whereas the experimental residual strain is higher than that predicted. Since both phenomena are governed by the same elastic parameters, the discrepancy cannot be explained by purely elastic analysis. Development of inelastic strains in the off-axis layer is suggested as a possible cause
|
|
| 26. |
- Kemppinen, A, et al.
(author)
-
MYO9B polymorphisms in multiple sclerosis
- 2009
-
In: European journal of human genetics : EJHG. - : Springer Science and Business Media LLC. - 1476-5438 .- 1018-4813. ; 17:6, s. 840-843
-
Journal article (peer-reviewed)
|
|
| 27. |
|
|
| 28. |
|
|
| 29. |
|
|
| 30. |
|
|
| 31. |
|
|
| 32. |
|
|
| 33. |
|
|
| 34. |
- Lundmark, Jöns, et al.
(author)
-
Paroxetine : pharmacokinetic and antidepressant effect in the elderly
- 1989
-
In: Acta Psychiatrica Scandinavica. - : Wiley. - 0001-690X .- 1600-0447. ; 80:S350, s. 76-80
-
Journal article (peer-reviewed)abstract
- To evaluate the pharmacokinetic properties, efficacy, and tolerability of paroxetine in elderly depressed patients, a clinical study was set up - initially at Aalborg Psychiatric Hospital in Denmark, and subsequently at the University Hospital in Linköping, Sweden. A total of 21 patients with a median age of 72 years were included in the study. After a single dose of 20 or 30mg of paroxetine followed by two drug-free days, treatment continued with 20 or 30mg daily for seven weeks. The majority of patients showed a continuous reduction in their HAMD scores, starting in the second week of treatment. Paroxetine was well tolerated at the doses given, and side-effects were mostly mild and transient. Steady-state, pre-dose plasma levels of paroxetine showed considerable variability, and the median steady-state concentration was higher in elderly patients compared with data from a previous study in young volunteers. Elimination half-lives also showed variability between these elderly patients, but tended to be longer after cessation of multiple dosing than after a single dose. They also tended to be longer than in the young volunteers. The results of this study do not advocate reduced doses of paroxetine in the elderly, but further studies are warranted.
|
|
| 35. |
|
|
| 36. |
- Lundmark, Katarzyna, et al.
(author)
-
Depletion of Spleen Macrophages Delays AA Amyloid Development: A Study Performed in the Rapid Mouse Model of AA Amyloidosis
- 2013
-
In: PLOS ONE. - : Public Library of Science. - 1932-6203. ; 8:11, s. e79104-
-
Journal article (peer-reviewed)abstract
- AA amyloidosis is a systemic disease that develops secondary to chronic inflammatory diseases Macrophages are often found in the vicinity of amyloid deposits and considered to play a role in both formation and degradation of amyloid fibrils. In spleen reside at least three types of macrophages, red pulp macrophages (RPM), marginal zone macrophages (MZM), metallophilic marginal zone macrophages (MMZM). MMZM and MZM are located in the marginal zone and express a unique collection of scavenger receptors that are involved in the uptake of blood-born particles. The murine AA amyloid model that resembles the human form of the disease has been used to study amyloid effects on different macrophage populations. Amyloid was induced by intravenous injection of amyloid enhancing factor and subcutaneous injections of silver nitrate and macrophages were identified with specific antibodies. We show that MZMs are highly sensitive to amyloid and decrease in number progressively with increasing amyloid load. Total area of MMZMs is unaffected by amyloid but cells are activated and migrate into the white pulp. In a group of mice spleen macrophages were depleted by an intravenous injection of clodronate filled liposomes. Subsequent injections of AEF and silver nitrate showed a sustained amyloid development. RPMs that constitute the majority of macrophages in spleen, appear insensitive to amyloid and do not participate in amyloid formation.
|
|
| 37. |
- Lundmark, Katarzyna, et al.
(author)
-
Naturally occurring fibrillar proteins can induce AA amyloidosis by a prion-like mechanism
-
Other publication (other academic/artistic)abstract
- Experimental AA amyloidosis, where the acute phase protein serum AA (SAA) forms amyloid fibrils, can be induced in mice provoked with inflannnatmy challenge. The time for development of amyloid is dramatically shortened when the animals concomitantly receive extract of a tissue from another mouse with amyloid 1-3. The active elusive principle has been named Amyloid Enhancing Factor (AEF) and experimental secondary amyloidosis was supposed to be a nucleation dependent process. The nature of the nucleus, however, was unknown for a long time. Our studies with synthetic amyloid-like fibrils made frmn short amyloidogenic pep tides instead of AEF 4, 5, indicate that the amyloid fibrils theruselves may act as nuclei for fibril formation (Fig. 1a). Here we present the enhanced development of AA -amyloidosis by naturally occurring amyloid-like protein fibrils.
|
|
| 38. |
|
|
| 39. |
- Lundmark, Katarzyna, et al.
(author)
-
Transmissibility of systemic amyloidosis by a prion-like mechanism
- 2002
-
In: Proceedings of the National Academy of Sciences of the United States of America. - : Proceedings of the National Academy of Sciences. - 0027-8424 .- 1091-6490. ; 99:10, s. 6979-6984
-
Journal article (peer-reviewed)abstract
- The generation of amyloid fibrils from an amyloidogenic polypeptide occurs by a nucleation-dependent process initiated in vitro by seeding the protein solution with preformed fibrils. This phenomenon is evidenced in vivo by the fact that amyloid protein A (AA) amyloidosis in mice is markedly accelerated when the animals are given, in addition to an inflammatory stimulus, an i.v. injection of protein extracted from AA amyloid-laden mouse tissue. Heretofore, the chemical nature of this “amyloid enhancing factor” (AEF) has not been definitively identified. Here we report that the active principle of AEF extracted from the spleen of mice with silver nitrate-induced AA amyloidosis was identified unequivocally as the AA fibril itself. Further, we demonstrated that this material was extremely potent, being active in doses <1 ng, and that it retained its biologic activity over a considerable length of time. Notably, the AEF was also effective when administered orally. Our studies have provided evidence that AA and perhaps other forms of amyloidosis are transmissible diseases, akin to the prion-associated disorders.
|
|
| 40. |
|
|
| 41. |
- Lundmark, Richard, et al.
(author)
-
Arf family GTP loading is activated by, and generates, positive membrane curvature.
- 2008
-
In: The Biochemical journal. - 1470-8728. ; 414:2, s. 189-94
-
Journal article (peer-reviewed)abstract
- Small G-proteins belonging to the Arf (ADP-ribosylation factor) family serve as regulatory proteins for numerous cellular processes through GTP-dependent recruitment of effector molecules. In the present study we demonstrate that proteins in this family regulate, and are regulated by, membrane curvature. Arf1 and Arf6 were shown to load GTP in a membrane-curvature-dependent manner and stabilize, or further facilitate, changes in membrane curvature through the insertion of an amphipathic helix.
|
|
| 42. |
|
|
| 43. |
|
|
| 44. |
|
|
| 45. |
|
|
| 46. |
|
|
| 47. |
- Nandadasa, Sumeda, et al.
(author)
-
A new mouse mutant with cleavage-resistant versican and isoform-specific versican mutants demonstrate that proteolysis at the Glu441-Ala442 peptide bond in the V1 isoform is essential for interdigital web regression
- 2021
-
In: Matrix Biology Plus. - : Elsevier BV. - 2590-0285. ; 10
-
Journal article (peer-reviewed)abstract
- Two inherent challenges in the mechanistic interpretation of protease-deficient phenotypes are defining the specific substrate cleavages whose reduction generates the phenotypes and determining whether the phenotypes result from loss of substrate function, substrate accumulation, or loss of a function(s) embodied in the substrate fragments. Hence, recapitulation of a protease-deficient phenotype by a cleavage-resistant substrate would stringently validate the importance of a proteolytic event and clarify the underlying mechanisms. Versican is a large proteoglycan required for development of the circulatory system and proper limb development, and is cleaved by ADAMTS proteases at the Glu441-Ala442 peptide bond located in its alternatively spliced GAGβ domain. Specific ADAMTS protease mutants have impaired interdigit web regression leading to soft tissue syndactyly that is associated with reduced versican proteolysis. Versikine, the N-terminal proteolytic fragment generated by this cleavage, restores interdigit apoptosis in ADAMTS mutant webs. Here, we report a new mouse transgene, VcanAA, with validated mutations in the GAGβ domain that specifically abolish this proteolytic event. VcanAA/AA mice have partially penetrant hindlimb soft tissue syndactyly. However, Adamts20 inactivation in VcanAA/AA mice leads to fully penetrant, more severe syndactyly affecting all limbs, suggesting that ADAMTS20 cleavage of versican at other sites or of other substrates is an additional requirement for web regression. Indeed, immunostaining with a neoepitope antibody against a cleavage site in the versican GAGα domain demonstrated reduced staining in the absence of ADAMTS20. Significantly, mice with deletion of Vcan exon 8, encoding the GAGβ domain, consistently developed soft tissue syndactyly, whereas mice unable to include exon 7, encoding the GAGα domain in Vcan transcripts, consistently had fully separated digits. These findings suggest that versican is cleaved within each GAG-bearing domain during web regression, and affirms that proteolysis in the GAGβ domain, via generation of versikine, has an essential role in interdigital web regression.
|
|
| 48. |
|
|
| 49. |
|
|
| 50. |
- Panahi, Aida Vahdat Shariat, et al.
(author)
-
Lipid membranes accelerate amyloid formation in the mouse model of AA amyloidosis
- 2019
-
In: Amyloid. - : Informa UK Limited. - 1350-6129 .- 1744-2818. ; 26:1, s. 34-44
-
Journal article (peer-reviewed)abstract
- Introduction:AA amyloidosis develops as a result of prolonged inflammation and is characterized by deposits of N-terminal proteolytic fragments of the acute phase reactant serum amyloid A (SAA). Macrophages are usually found adjacent to amyloid, suggesting their involvement in the formation and/or degradation of the amyloid fibrils. Furthermore, accumulating evidence suggests that lipid membranes accelerate the fibrillation of different amyloid proteins.Methods:Using an experimental mouse model of AA amyloidosis, we compared the amyloidogenic effect of liposomes and/or amyloid-enhancing factor (AEF). Inflammation was induced by subcutaneous injection of silver nitrate followed by intravenous injection of liposomes and/or AEF to accelerate amyloid formation.Results:We showed that liposomes accelerate amyloid formation in inflamed mice, but the amyloidogenic effect of liposomes was weaker compared with AEF. Regardless of the induction method, amyloid deposits were mainly found in the marginal zones of the spleen and coincided with the depletion of marginal zone macrophages, while red pulp macrophages and metallophilic marginal zone macrophages proved insensitive to amyloid deposition.Conclusions:We conclude that increased intracellular lipid content facilitates AA amyloid fibril formation and show that the mouse model of AA amyloidosis is a suitable system for further mechanistic studies.
|
|
