| 1. |
- Svensson, Mattias, 1982, et al.
(author)
-
Fms-like tyrosine kinase 3 ligand controls formation of regulatory T cells in autoimmune arthritis.
- 2013
-
In: PloS one. - : Public Library of Science (PLoS). - 1932-6203. ; 8:1
-
Journal article (peer-reviewed)abstract
- Fms-like tyrosine kinase 3 ligand (Flt3L) is known as the primary differentiation and survival factor for dendritic cells (DCs). Furthermore, Flt3L is involved in the homeostatic feedback loop between DCs and regulatory T cell (Treg). We have previously shown that Flt3L accumulates in the synovial fluid in rheumatoid arthritis (RA) and that local exposure to Flt3L aggravates arthritis in mice, suggesting a possible involvement in RA pathogenesis. In the present study we investigated the role of Flt3L on DC populations, Tregs as well as inflammatory responses in experimental antigen-induced arthritis. Arthritis was induced in mBSA-immunized mice by local knee injection of mBSA and Flt3L was provided by daily intraperitoneal injections. Flow cytometry analysis of spleen and lymph nodes revealed an increased formation of DCs and subsequently Tregs in mice treated with Flt3L. Flt3L-treatment was also associated with a reduced production of mBSA specific antibodies and reduced levels of the pro-inflammatory cytokines IL-6 and TNF-α. Morphological evaluation of mBSA injected joints revealed reduced joint destruction in Flt3L treated mice. The role of DCs in mBSA arthritis was further challenged in an adoptive transfer experiment. Transfer of DCs in combination with T-cells from mBSA immunized mice, predisposed naïve recipients for arthritis and production of mBSA specific antibodies. We provide experimental evidence that Flt3L has potent immunoregulatory properties. Flt3L facilitates formation of Treg cells and by this mechanism reduces severity of antigen-induced arthritis in mice. We suggest that high systemic levels of Flt3L have potential to modulate autoreactivity and autoimmunity.
|
|
| 2. |
- Andersson, Sofia E M, 1979, et al.
(author)
-
Activation of Fms-like tyrosine kinase 3 signaling enhances survivin expression in a mouse model of rheumatoid arthritis.
- 2012
-
In: PloS one. - : Public Library of Science (PLoS). - 1932-6203. ; 7:10
-
Journal article (peer-reviewed)abstract
- Survivin is known as an inhibitor of apoptosis and a positive regulator of cell division. We have recently identified survivin as a predictor of joint destruction in patients with rheumatoid arthritis (RA). Flt3 ligand (Flt3L) is expressed in the inflamed joints and has adjuvant properties in arthritis. Studies on 90 RA patients (median age 60.5 years [range, 24-87], disease duration 10.5 years [range, 0-35]) show a strong positive association between the levels of survivin and Flt3L in blood. Here, we present experimental evidence connecting survivin and Flt3L signaling. Treatment of BALB/c mice with Flt3L led to an increase of survivin in the bone marrow and in splenic dendritic cells. Flt3L changed the profile of survivin splice variants, increasing transcription of the short survivin40 in the bone marrow. Treatment with an Flt3 inhibitor reduced total survivin expression in bone marrow and in the dendritic cell population in spleen. Inhibition of survivin transcription in mice, by shRNA lentiviral constructs, reduced the gene expression of Flt3L. We conclude that expression of survivin is a downstream event of Flt3 signaling, which serves as an essential mechanism supporting survival of leukocytes during their differentiation, and maturation of dendritic cells, in RA.
|
|
| 3. |
- Erlandsson, Malin, 1972, et al.
(author)
-
Expression of metastasin S100A4 is essential for bone resorption and regulates osteoclast function.
- 2013
-
In: Biochimica et biophysica acta. - : Elsevier BV. - 0006-3002. ; 1833:12, s. 2653-2663
-
Journal article (peer-reviewed)abstract
- S100A4 is a Ca-binding protein that regulates cell growth, survival, and motility. The abundant expression of S100A4 in rheumatiod arthritis contributes to the invasive growth of joint tissue and to bone damage. In the present study, we analysed the role of S100A4 in bone homeostasis.
|
|
| 4. |
- Brisslert, Mikael, 1974, et al.
(author)
-
S100A4 regulates the Src-tyrosine kinase dependent differentiation of Th17 cells in rheumatoid arthritis
- 2014
-
In: Biochimica Et Biophysica Acta-Molecular Basis of Disease. - : Elsevier BV. - 0925-4439. ; 1842:11, s. 2049-2059
-
Journal article (peer-reviewed)abstract
- Objectives: To evaluate the role of S100A4, a calcium-binding regulator of nonmuscle myosin assembly, for T-cell responses in rheumatoid arthritis. Methods: Arthritis was induced in the methylated bovine serum albumin (mBSA)-immunized mice lacking the entire S100A4 protein (S100A4KO) and in wild-type counterparts treated with short hairpin ribonucleic acid (shRNA)-lentiviral constructs targeting S100A4 (S100A4-shRNA). The severity of arthritis was evaluated morphologically. T-cell subsets were characterized by the expression of master transcription factors, and functionally by proliferation activity and cytokine production. The activity of the Scr-kinases Fyn and Lck was assessed by the autophosphorylation of C-terminal thyrosine and by the phosphorylation of the CD5 cytodomain. The interaction between S100A4 and the CD5 cytodomain was analysed by nuclear magnetic resonance spectrophotometry. Results: S100A4-deficient mice (S100A4KO and S100A4-shRNA) had significantly alleviated morphological signs of arthritis and joint damage. Leukocyte infiltrates in the arthritic joints of S100A4-deficient mice accumulated Foxp3(+) Treg cells, while the number of ROR gamma t(+) and (pTyr705)STAT3(+) cells was reduced. S100A4-deficient mice had a limited formation of Th17-cells with low retinoic acid orphan receptor gamma t (ROR gamma t) mRNA and IL17 production in T-cell cultures. S100A4-deficient mice had a low expression and activity of T-cell receptor (TCR) inhibitor CD5 and low (pTyr705)STAT3 (signal transducer and activator of transcription 3), which led to increased (pTyr352)ZAP-70 (theta-chain associated protein kinase of 70 kDa), lymphocyte proliferation and production of IL2. In vitro experiments showed that S100A4 directly binds Lck and Fyn and reciprocally regulates their kinase activity towards the CD5 cytodomain. Spectrometry demonstrates an interaction between the CD5 cytodomain and EF2-binding sites of S100A4. Conclusion: The present. study demonstrates that S100A4 plays an important part in the pathogenesis of arthritis. It controls CD5-dependent differentiation of Th17 cells by regulating the activity of the Src-family kinases Lck and Fyn. (C) 2014 Elsevier B.V. All rights reserved.
|
|
| 5. |
- Erlandsson, Malin, 1972, et al.
(author)
-
Metastasin S100A4 is a mediator of sex hormone-dependent formation of the cortical bone.
- 2013
-
In: Molecular endocrinology (Baltimore, Md.). - : The Endocrine Society. - 1944-9917 .- 0888-8809. ; 27:8, s. 1311-21
-
Journal article (peer-reviewed)abstract
- S100A4 is a Ca-binding protein participating in regulation of cell growth, survival, and motility. Here we studied the role of S100A4 protein in sex hormone-regulated bone formation. Bone mineral density in the trabecular and cortical compartments was evaluated in female S100A4 knockout (KO), in matched wild-type (WT) counterparts, and in WT mice treated with lentiviral small hairpin RNA construct inhibiting the S100A4 gene transcription or with a nontargeting construct, by peripheral quantitative computed tomography. The effect of sex hormones on bone was measured 5 weeks after ovariectomy (OVX) and/or dehydroepiadrosterone treatment. S100A4KO had an excessive trabecular and cortical bone formation compared with the age- and sex-matched WT mice. S100A4KO had an increased periosteal circumference (P = .001), cortical thickness (P = .056), and cortical area (P = .003), which predicted 20% higher bone strength in S100A4KO (P = .013). WT mice treated with small hairpin RNA-S100A4 showed an increase of the cortical bone parameters in a fashion identical with S100A4KO mice, indicating the key role of S100A4 in the changed bone formation. S100A4KO mice had higher serum levels of osteocalcin and a higher number of osteocalcin-positive osteoblasts under the periosteum. OVX-S100A4 resulted in the loss of the cortical bone supported by high CTX-I levels, whereas no such changes were observed in OVX-WT mice. S100A4KO mice resisted the dehydroepiadrosterone -induced bone formation observed in the WT counterparts. Our study indicates that S100A4 is a regulator of bone formation, which inhibits bone excess in the estrogen-sufficient mice and prevents the cortical bone loss in the estrogen-deprived mice.
|
|
| 6. |
- Liu, Meng, 1976, et al.
(author)
-
Targeting the protein prenyltransferases efficiently reduces tumor development in mice with K-RAS-induced lung cancer
- 2010
-
In: Proceedings of the National Academy of Sciences of the United States of America. - : Proceedings of the National Academy of Sciences. - 0027-8424. ; 107:14, s. 6471-6476
-
Journal article (peer-reviewed)abstract
- RAS and RHO proteins, which contribute to tumorigenesis and metastasis, undergo posttranslational modification with an isoprenyl lipid by protein farnesyltransferase (FTase) or protein geranylgeranyltransferase-I (GGTase-I). Inhibitors of FTase and GGTase-I were developed to block RAS-induced malignancies, but their utility has been difficult to evaluate because of off-target effects, drug resistance, and toxicity. Moreover, the impact of FTase deficiency and combined FTase/GGTase-I deficiency has not been evaluated with genetic approaches. We found that inactivation of FTase eliminated farnesylation of HDJ2 and H-RAS, prevented H-RAS targeting to the plasma membrane, and blocked proliferation of primary and K-RAS(G12D)-expressing fibroblasts. FTase inactivation in mice with K-RAS-induced lung cancer reduced tumor growth and improved survival, similar to results obtained previously with inactivation of GGTase-I. Simultaneous inactivation of FTase and GGTase-I markedly reduced lung tumors and improved survival without apparent pulmonary toxicity. These data shed light on the biochemical and therapeutic importance of FTase and suggest that simultaneous inhibition of FTase and GGTase-I could be useful in cancer therapeutics.
|
|
| 7. |
|
|
| 8. |
- Almlöv, Jonas, et al.
(author)
-
Therapist effects in guided internet-delivered CBT for Anxiety Disorders
- 2011
-
In: Behavioural and Cognitive Psychotherapy. - London : Wisepress. - 1352-4658 .- 1469-1833. ; 39:3, s. 311-322
-
Journal article (peer-reviewed)abstract
- Background: Guided internet-delivered CBT for anxiety disorders has received increasing empirical support, but little is known regarding the role of the therapist. Aims: This study addressed therapist factors in guided internet-delivered cognitive behavioural therapy for anxiety disorders. Method: Data from three controlled trials with a total N of 119 were analyzed with attention to differences between eight therapists. Results: No significant mean level differences between therapists appeared in the dataset. However, one significant intraclass correlation between participants was found, suggesting that the outcome on the Beck Anxiety Inventory might have been influenced by the impact of the individual therapists. Conclusion: The therapist can possibly have some influence on the outcome of guided internet-delivered CBT for anxiety disorders, but studies with more statistical power are needed to establish whether therapist effects are present in this modality of psychological treatment. The present study was underpowered to detect minor therapist effects.
|
|
| 9. |
- Baldi, Francesco, 1986, et al.
(author)
-
Analysis of the influence of the engine, propeller and auxiliary generation interaction on the energy efficiency of controllable pitch propeller ships
- 2014
-
In: International Conference of Maritime Technology.
-
Conference paper (peer-reviewed)abstract
- In a context of increasing requirements for energy efficiency, this paper aims at improving theunderstanding on the interaction between engine, propeller, and auxiliary heat and power generation in theparticular case of controllable pitch propeller (CPP) ships. The case study of a CPP propelled chemical tankeris used to analyze the application of the proposed approach. The performance of the ship’s standardarrangement using a shaft generator for the fulfillment of auxiliary power demand is compared to theoperational alternative of using auxiliary engines, and with the possibilities for retrofitting with frequencyconverters and waste heat recovery systems. The influence of control systems parameters and of sea state arealso analyzed and compared. The results show a large possibility for improvements, both via operationaloptimization (up to 8.3% increased energy efficiency) and via different types of retrofitting (with increasedefficiencies of up to 11.4% for frequency converters, and 16.5% for WHR systems). The influence of a broadoperational envelope brings even larger improvements to the efficiency of the energy system at low speeds. Theresults of the paper provide useful information about the influence of different technologies for auxiliary powergeneration on the efficiency of CPP propelled vessels.
|
|
| 10. |
- Jonsson, Anna, et al.
(author)
-
Cities’ capacity to manage climate vulnerability : experiences from participatory vulnerability assessments in the lower Göta Älv Catchment, Sweden
- 2012
-
In: Local Environment. - : Routledge. - 1354-9839 .- 1469-6711. ; 17:6-7, s. 735-750
-
Journal article (peer-reviewed)abstract
- Within the scope of this project, tools for conducting systematic and integrated climate vulnerability and sustainability assessments have been developed. Two municipalities in the lower Göta Älv catchment were selected as study cases. Together with representatives from key municipal departments and national government agencies, the interdisciplinary research team designed and conducted a co-production process. Results obtained using the developed tools demonstrate that conducting such a systematic assessment of the current situation and potential impacts of climate change adaptation measures would contribute to synergies between adaptation strategies and other policy arenas. Our recommendation for enhancing the capacity of local vulnerability management in Sweden is to shift foci in four fields: from static analysis of climate vulnerability to a dynamic approach to social vulnerability, from a sectorwise fragmented approach to integrated management, from a focus on technical fixes and physical measures to institutional adaptation measures, and, finally, from sustainability-blind adaptation investments to long-term sustainable climate adaptation measures. The processes and mechanisms for succeeding in this requires that knowledge be produced, shared, and managed in partly new ways, allowing stakeholders both inside and outside local government administration to voice and synergise their concerns and solutions.
|
|
