| 1. |
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| 2. |
- Bobbio, Emanuele, et al.
(författare)
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Clinical Diagnosis and Subtyping of Cardiac Amyloidosis by Mass Spectrometry.
- 2020
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Ingår i: The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation. - : Elsevier BV. - 1557-3117. ; 39:4S
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Tidskriftsartikel (refereegranskat)abstract
- Medical treatment for cardiac amyloidosis (CA) is evolving rapidly. Heart transplantation can be a valid option when followed by transplantation of bone marrow or liver, dependent on the type and origin of the amyloid protein. Thus, accurate typing of amyloidosis has implications for treatment, prognosis, and genetic counseling. Although non-invasive diagnostic techniques can type CA, endomyocardial biopsy (EMB) may be needed in the case of equivocal imaging findings or discordant data. We aimed to define the role of mass spectrometry (MS) for diagnosis and subtyping of CA.Nineteen previously diagnosed CA cases, who underwent EMB at Sahlgrenska University Hospital (SU), Gothenburg, between the beginning 1990s and 2016, were selected. MS analysis, modified from was conducted on duplicate samples from myocardial tissue for each case included.1 Clinical features and diagnoses were used as gold standard and compared to the MS findings.Clinical diagnosis and the MS analysis agreed in 14 cases (73.7 %); in 3/19 (15.8 %) diagnosis was unclear or discordant (Fig.1). MS analysis revealed that transthyretin (TTR) amyloidosis was the most abundant amyloid protein in the samples examined (9/19; 47.3 %), whereas the AA subtype only occurred in 1 case (5.2 %). The AL κ type amyloidosis occurred in 3 cases (15.8 %), and AL λ type in six cases (31.6 %). These results strongly correlated with the clinical features in all patients. Clinical diagnosis could not be retrieved from the medical records in 2 cases (10.4 %). Additional 20 patients with clinical CA are presently under study.MS analysis of a small amount of endomyocardial tissue can be used to subtype CA with a high diagnostic validity. The method differentiated between TTR, SAA and Ig light chain amyloidosis. AL κ and AL λ identities correlated to those found in serum and urine electrophoreses. MS can therefore be of use to subtype CA for cases in which clinical findings are inconclusive. 1) Brambilla F et al. Blood. 2012 Feb 23;119(8):1844-7.
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| 3. |
- Burney, P., et al.
(författare)
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A case-control study of the relation between plasma selenium and asthma in European populations : a GAL2EN project
- 2008
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Ingår i: Allergy. European Journal of Allergy and Clinical Immunology. - : Wiley. - 0105-4538 .- 1398-9995. ; 63:7, s. 865-871
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: There is evidence that selenium levels are relatively low in Europe and may be falling. Low levels of selenium or low activity of some of the enzymes dependent on selenium have been associated with asthma. METHODS: The GA(2)LEN network has organized a multicentre case-control study in Europe to assess the relation of plasma selenium to asthma. The network compared 569 cases in 14 European centres with a diagnosis of asthma and reporting asthma symptoms in the last 12 months with 576 controls from the same centres with no diagnosis of asthma and no asthmatic symptoms in the last 12 months. RESULTS: All cases and controls were selected from the same population defined by age and place of residence. Mean plasma selenium concentrations among the controls ranged from 116.3 microg/l in Palermo to 67.7 microg/l in Vienna and 56.1 microg/l among the children in Oslo. Random effects meta-analysis of the results from the centres showed no overall association between asthma and plasma selenium [odds ratio (OR)/10 microg/l increase in plasma selenium: 1.04; 95% confidence interval (CI): 0.89-1.21] though there was a significantly protective effect in Lodz (OR: 0.48; 95% CI: 0.29-0.78) and a marginally significant adverse effect in Amsterdam (OR: 1.68; 95% CI: 0.98-2.90) and Ghent (OR: 1.35; 95% CI: 1.03-1.77). CONCLUSION: This study does not support a role for selenium in protection against asthma, but effect modification and confounding cannot be ruled out.
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| 4. |
- Elgali, Ibrahim, et al.
(författare)
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Guided bone regeneration: materials and biological mechanisms revisited
- 2017
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Ingår i: European Journal of Oral Sciences. - : Wiley. - 0909-8836. ; 125:5, s. 315-337
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Forskningsöversikt (refereegranskat)abstract
- Guided bone regeneration (GBR) is commonly used in combination with the installment of titanium implants. The application of a membrane to exclude non-osteogenic tissues from interfering with bone regeneration is a key principle of GBR. Membrane materials possess a number of properties which are amenable to modification. A large number of membranes have been introduced for experimental and clinical verification. This prompts the need for an update on membrane properties and the biological outcomes, as well as a critical assessment of the biological mechanisms governing bone regeneration in defects covered by membranes. The relevant literature for this narrative review was assessed after a MEDLINE/PubMed database search. Experimental data suggest that different modifications of the physicochemical and mechanical properties of membranes may promote bone regeneration. Nevertheless, the precise role of membrane porosities for the barrier function of GBR membranes still awaits elucidation. Novel experimental findings also suggest an active role of the membrane compartment per se in promoting the regenerative processes in the underlying defect during GBR, instead of being purely a passive barrier. The optimization of membrane materials by systematically addressing both the barrier and the bioactive properties is an important strategy in this field of research.
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| 5. |
- Elgali, Ibrahim, et al.
(författare)
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Guided bone regeneration using resorbable membrane and different bone substitutes : Early histological and molecular events
- 2016
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Ingår i: Acta Biomaterialia. - : Elsevier BV. - 1742-7061 .- 1878-7568. ; 29, s. 409-423
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Tidskriftsartikel (refereegranskat)abstract
- Bone insufficiency remains a major challenge for bone-anchored implants. The combination of guided bone regeneration (GBR) and bone augmentation is an established procedure to restore the bone. However, a proper understanding of the interactions between the bone substitute and GBR membrane materials and the bone-healing environment is lacking. This study aimed to investigate the early events of bone healing and the cellular activities in response to a combination of GBR membrane and different calcium phosphate (CaP) materials. Defects were created in the trabecular region of rat femurs, and filled with deproteinized bovine bone (DBB), hydroxyapatite (HA) or strontium-doped HA (SrHA) or left empty (sham). All the defects were covered with an extracellular matrix membrane. Defects were harvested after 12 h, 3 d and 6 d for histology/histomorphometry, immunohistochemistry and gene expression analyses. Histology revealed new bone, at 6 d, in all the defects. Larger amount of bone was observed in the SrHA-filled defect. This was in parallel with the reduced expression of osteoclastic genes (CR and CatK) and the osteoblast-osteoclast coupling gene (RANKL) in the SrHA defects. Immunohistochemistry indicated fewer osteoclasts in the SrHA defects. The observations of CD68 and periostin-expressing cells in the membrane per se indicated that the membrane may contribute to the healing process in the defect. It is concluded that the bone-promoting effects of Sr in vivo are mediated by a reduction in catabolic and osteoblast-osteoclast coupling processes. The combination of a bioactive membrane and CaP bone substitute material doped with Sr may produce early synergistic effects during GBR. Statement of significance The study provides novel molecular, cellular and structural evidence on the promotion of early bone regeneration in response to synthetic strontium-containing hydroxyapatite (SrHA) substitute, in combination with a resorbable, guided bone regeneration (GBR) membrane. The prevailing view, based mainly upon in vitro data, is that the beneficial effects of Sr are exerted by the stimulation of bone-forming cells (osteoblasts) and the inhibition of bone-resorbing cells (osteoclasts). In contrast, the present study demonstrates that the local effect of Sr in vivo is predominantly via the inhibition of osteoclast number and activity and the reduction of osteoblast-osteoclast coupling. This experimental data will form the basis for clinical studies, using this material as an interesting bone substitute for guided bone regeneration.
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| 6. |
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| 7. |
- Grandfield, Kathryn, et al.
(författare)
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Bone response to free form fabricated hydroxyapatite and zirconia scaffolds : a transmission electron microscopy study in the human maxilla
- 2012
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Ingår i: Clinical Implant Dentistry and Related Research. - : Wiley. - 1523-0899 .- 1708-8208. ; 14:3, s. 461-469
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Tidskriftsartikel (refereegranskat)abstract
- Background: Understanding the interfacial reactions to synthetic bone regenerative scaffolds in vivo is fundamental for improving osseointegration and osteogenesis. Using transmission electron microscopy, it is possible to study the biological response of hydroxyapatite (HA) and zirconia (ZrO2) scaffolds at the nanometer scale.Purpose: In this study, the bone-bonding abilities of HA and ZrO2 scaffolds produced by free-form fabrication were evaluated in the human maxilla at 3 months and 7 months.Materials and Methods: HA and ZrO2 scaffolds (ø: 3 mm) were implanted in the human maxilla, removed with surrounding bone, embedded in resin, and sectioned. A novel focused ion beam (FIB) sample preparation technique enabled the production of thin lamellae for study by scanning transmission electron microscopy.Results: Interface regions were investigated using high-angle annular dark-field imaging and energy-dispersive X-ray spectroscopy analysis. Interfacial apatite layers of 80 nm and 50 nm thickness were noted in the 3- and 7-month HA samples, respectively, and bone growth was discovered in micropores up to 10 µm into the samples.Conclusions: The absence of an interfacial layer in the ZrO2 samples suggest the formation of a direct contact with bone, while HA, which bonds through an apatite layer, shows indications of resorption with increasing implantation time. This study demonstrates the potential of HA and ZrO2 scaffolds for use as bone regenerative materials.
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| 8. |
- Gurgel-Giannetti, J., et al.
(författare)
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A novel complex neurological phenotype due to a homozygous mutation in FDX2
- 2018
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Ingår i: Brain. - : Oxford University Press (OUP). - 0006-8950 .- 1460-2156. ; 141, s. 2289-2298
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Tidskriftsartikel (refereegranskat)abstract
- Defects in iron-sulphur [Fe-S] cluster biogenesis are increasingly recognized as causing neurological disease. Mutations in a number of genes that encode proteins involved in mitochondrial [Fe-S] protein assembly lead to complex neurological phenotypes. One class of proteins essential in the early cluster assembly are ferredoxins. FDX2 is ubiquitously expressed and is essential in the de novo formation of [2Fe-2S] clusters in humans. We describe and genetically define a novel complex neurological syndrome identified in two Brazilian families, with a novel homozygous mutation in FDX2. Patients were clinically evaluated, underwent MRI, nerve conduction studies, EMG and muscle biopsy. To define the genetic aetiology, a combination of homozygosity mapping and whole exome sequencing was performed. We identified six patients from two apparently unrelated families with autosomal recessive inheritance of a complex neurological phenotype involving optic atrophy and nystagmus developing by age 3, followed by myopathy and recurrent episodes of cramps, myalgia and muscle weakness in the first or second decade of life. Sensory-motor axonal neuropathy led to progressive distal weakness. MRI disclosed a reversible or partially reversible leukoencephalopathy. Muscle biopsy demonstrated an unusual pattern of regional succinate dehydrogenase and cytochrome c oxidase deficiency with iron accumulation. The phenotype was mapped in both families to the same homozygous missense mutation in FDX2 (c. 431C > T, p. P144L). The deleterious effect of the mutation was validated by real-time reverse transcription polymerase chain reaction and western blot analysis, which demonstrated normal expression of FDX2 mRNA but severely reduced expression of FDX2 protein in muscle tissue. This study describes a novel complex neurological phenotype with unusual MRI and muscle biopsy features, conclusively mapped to a mutation in FDX2, which encodes a ubiquitously expressed mitochondrial ferredoxin essential for early [Fe-S] cluster biogenesis.
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| 9. |
- Göthberg, Catharina, 1960, et al.
(författare)
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Bone and soft tissue outcomes, risk factors, and complications of implant-supported prostheses: 5-Years RCT with different abutment types and loading protocols
- 2018
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Ingår i: Clinical Implant Dentistry and Related Research. - : Wiley. - 1523-0899 .- 1708-8208. ; 20:3, s. 313-321
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Tidskriftsartikel (refereegranskat)abstract
- BackgroundData on risk factors and complications after long-term implant treatment is limited. The aims were to evaluate the role of various fixation modes and to analyze complications and risks that affect long-term use of implant-supported partial fixed dental prostheses. Materials and MethodsFifty partially edentulous subjects received three Branemark TiUnite implants. Superstructures were attached directly at implant level (IL) or via abutments: machined surface (AM) and an oxidized surface (AOX, TiUnite). Implants were immediately loaded (test) or unloaded for 3 months (control). Examinations occurred over a 5-year period. ResultsForty-four subjects were re-examined after 5 years. Cumulative survival rates in test and control groups were 93.9% and 97.0%, respectively. Marginal bone loss (MBL; Mean [SEM]) was significantly lower at superstructures connected to AM (1.61 [0.25] mm) than at sites with no abutment IL (2.14 [0.17] mm). Peri-implantitis occurred in 9.1% of subjects and in 4.0% of implants. Multiple linear regression indicated that increased probing pocket depth (PPD), periodontal disease experience, deteriorating health, and light smoking (10 cigarettes/day) predict greater MBL, whereas increased buccal soft tissue thickness and higher ISQ predict lower MBL. ConclusionsThe results show that MBL was influenced by the connection type. A machined abutment, instead of connecting the superstructure directly at the implant level, was beneficial. The following factors influenced MBL: PPD, periodontal disease experience, deteriorating health, light smoking, buccal soft tissue thickness, and ISQ. The results on peri-implantitis underscore the need for long-term maintenance care. Further, the abutment material surface properties constitute additional target for strategies to minimize MBL.
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| 10. |
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| 11. |
- Göthberg, Catharina, 1960, et al.
(författare)
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Immediately Loaded Implants with or without Abutments Supporting Fixed Partial Dentures: 1-Year Results from a Prospective, Randomized, Clinical Trial.
- 2014
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Ingår i: Clinical implant dentistry and related research. - : Wiley. - 1708-8208 .- 1523-0899. ; 16:4, s. 487-500
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Tidskriftsartikel (refereegranskat)abstract
- PURPOSE: To evaluate 1-year implant survival and marginal bone loss around implants that support fixed partial dentures loaded immediately or after 3 months, and effects from abutment usage. MATERIALS AND METHODS: In this 2005 to 2009 randomized, parallel-group, clinical trial, 50 partially edentulous patients each received three Brånemark TiUnite™ implants (Nobel Biocare®, Göteborg, Sweden), mostly in the posterior maxilla. Two implants were fitted with abutments: a TiUnite™ surface and a machine-milled surface; the suprastructure was attached directly at implant level for the third implant. After randomized allocation, implants were immediately loaded with a fixed temporary bridge (test group) or left unloaded for 3 months (control group). A permanent fixed suprastructure replaced the temporary bridge after 6 months (test). Hard and soft tissues were examined during pretreatment and surgery plus 2 days, 14 days, 4 weeks, 3 months, and 1 year after surgery. RESULTS: After 1 year, four implants were lost in the test and two in the control groups (1-year survival rates of 94.9% [test] and 97.2% [control], with no significant intergroup difference). Resonance frequency analysis values indicated a similar pattern in both groups, with implant stability quotient (ISQ) reduction between 2 and 4 weeks. The test group had a significantly lower ISQ than the control group at these appointments. After 1 year, marginal bone losses around the implants were, on average, 1.32mm (test, standard error of the mean [SEM] 0.08) and 1.24mm (control, SEM 0.08), with no significant intergroup difference. Significantly larger marginal bone loss was observed at implants without abutment compared with implants with abutment. CONCLUSIONS: For both groups, this study showed similar implant survival rates and marginal bone loss. Larger bone loss was found at implants loaded without attached abutments.
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| 12. |
- Jauhiainen, Alexandra, 1981, et al.
(författare)
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Distinct cytoplasmic and nuclear functions of the stress induced protein DDIT3/CHOP/GADD153
- 2012
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Ingår i: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 7:4
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Tidskriftsartikel (refereegranskat)abstract
- DDIT3, also known as GADD153 or CHOP, encodes a basic leucine zipper transcription factor of the dimer forming C/EBP family. DDIT3 is known as a key regulator of cellular stress response, but its target genes and functions are not well characterized. Here, we applied a genome wide microarray based expression analysis to identify DDIT3 target genes and functions. By analyzing cells carrying tamoxifen inducible DDIT3 expression constructs we show distinct gene expression profiles for cells with cytoplasmic and nuclear localized DDIT3. Of 175 target genes identified only 3 were regulated by DDIT3 in both cellular localizations. More than two thirds of the genes were downregulated, supporting a role for DDIT3 as a dominant negative factor that could act by either cytoplasmic or nuclear sequestration of dimer forming transcription factor partners. Functional annotation of target genes showed cell migration, proliferation and apoptosis/survival as the most affected categories. Cytoplasmic DDIT3 affected more migration associated genes, while nuclear DDIT3 regulated more cell cycle controlling genes. Cell culture experiments confirmed that cytoplasmic DDIT3 inhibited migration, while nuclear DDIT3 caused a G1 cell cycle arrest. Promoters of target genes showed no common sequence motifs, reflecting that DDIT3 forms heterodimers with several alternative transcription factors that bind to different motifs. We conclude that expression of cytoplasmic DDIT3 regulated 94 genes. Nuclear translocation of DDIT3 regulated 81 additional genes linked to functions already affected by cytoplasmic DDIT3. Characterization of DDIT3 regulated functions helps understanding its role in stress response and involvement in cancer and degenerative disorders.
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| 13. |
- Krokene, Paal, et al.
(författare)
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Pest risk categorization – New plant health regulations for Norway : Scientific Opinion of the Panel on Plant Health of the Norwegian Scientific Committee for Food and Environment
- 2021
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Rapport (refereegranskat)abstract
- In an ongoing effort to renew Norwegian regulations related to plants and measures against plant pests, the Norwegian Food Safety Authority asked The Norwegian Scientific Committee for Food and Environment (VKM) which of the currently regulated pests that should still be regulated (either as a quarantine pest (QP) or a regulated non-quarantine pest (RNQP) for Norway), and whether there are any species that should be deregulated. Following such a risk categorization process the Norwegian Food Safety Authority will determine if pest risk assessments (PRA’s) should be performed for quarantine pests. International trade regulations define quarantine pests (QPs) as pests of potential economic importance to an area that are not yet present, or are present but not widely distributed and are subject to official control. A regulated non-quarantine pest (RNQP) is a pest whose presence in plants for planting affects the intended use of those plants with an economically unacceptable impact and which is therefore subject to official control within the territory of the importing contracting party and regulated in international trade. In this report VKM presents an overview of the pest categorisation of some of the pests regulated in the current Norwegian regulation and concludes on whether each pest should be regulated as a potential QP, RNQP or none of these categories for Norway. The pest categorisation process – the process of determining whether a pest has or has not the characteristics of a QP or RNQP – has been done using the FinnPRIO model. The FinnPRIO model is a pest risk ranking tool that uses a hypervolume approach carry out quick, semiquantitative expert assessments and that allows a high number of pest risk categorizations to be done cost-effectively and in a short period of time. In total 33 pests were assessed as per request from the Norwegian Food Safety Authority. Of those 33 pests VKM suggests that the vast majority – 32 pests – are kept as a QPs for Norway. However, one pest, the cherry leafroll nepovirus (EPPO code CLRV00), fulfils the requirements for being a RNQP since it is most likely present in Norway already. Furthermore, one organism, the flatworm Arthurdendyus triangulates (ARDDTR), is suggested to not be regulated as QP or RNQP. This pest does not fulfil the requirements for being a QP since it would probably not cause direct damage to plants if it established in Norway. Also, it does not fulfill the requirements for being a regulated non-quarantine pest(RNQP) since its potential presence in plants for planting does not directly affect the intended use of those plants with an economically unacceptable impact.
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| 14. |
- Lindén, Malin, et al.
(författare)
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FET family fusion oncoproteins target the SWI/SNF chromatin remodeling complex
- 2019
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Ingår i: EMBO Reports. - : EMBO. - 1469-221X .- 1469-3178. ; 20
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Tidskriftsartikel (refereegranskat)abstract
- Members of the human FET family of RNA-binding proteins, comprising FUS, EWSR1, and TAF15, are ubiquitously expressed and engage at several levels of gene regulation. Many sarcomas and leukemias are characterized by the expression of fusion oncogenes with FET genes as 5′ partners and alternative transcription factor-coding genes as 3′ partners. Here, we report that the N terminus of normal FET proteins and their oncogenic fusion counterparts interact with the SWI/SNF chromatin remodeling complex. In contrast to normal FET proteins, increased fractions of FET oncoproteins bind SWI/SNF, indicating a deregulated and enhanced interaction in cancer. Forced expression of FET oncogenes caused changes of global H3K27 trimethylation levels, accompanied by altered gene expression patterns suggesting a shift in the antagonistic balance between SWI/SNF and repressive polycomb group complexes. Thus, deregulation of SWI/SNF activity could provide a unifying pathogenic mechanism for the large group of tumors caused by FET fusion oncoproteins. These results may help to develop common strategies for therapy. © 2019 The Authors. Published under the terms of the CC BY 4.0 license
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| 15. |
- Malmström, Johan, 1975, et al.
(författare)
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Bone response to free form-fabricated hydroxyapatite and zirconia scaffolds : A histological study in the human maxilla
- 2009
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Ingår i: Clinical Oral Implants Research. - : John Wiley & Sons. - 0905-7161 .- 1600-0501. ; 20:4, s. 379-385
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Tidskriftsartikel (refereegranskat)abstract
- Objectives: Synthetic and biological materials are increasingly used to provide temporary or permanent scaffolds for bone regeneration. This study evaluated the effect of material chemistry and microporosity on bone ingrowth and osseointegration of zirconia (ZrO2) and hydroxyapatite (HA) scaffolds in the human maxilla.Material and methods: Twelve patients subjected to dental implant placement were enrolled in the study. Scaffolds of ZrO 2 and HA were placed in the maxilla of each subject, using a randomization protocol. After 3 months of healing, biopsies were harvested comprising the scaffolds and surrounding bone tissue. The biopsies were processed for histological evaluation and morphometric analysis (bone ingrowth and bone-to-scaffold contact).Results: Healing was uneventful in all cases. All scaffolds demonstrated a measurable bone response using light microscopy and scanning electron microscopy. Microporous HA scaffolds revealed four times larger bone ingrowth and seven times larger bone contact as compared with ZrO2 scaffolds.Conclusion: The results show that chemistry and microporosity of HA promote bone ingrowth and bone contact of ceramic scaffolds in human maxilla.
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| 16. |
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| 17. |
- Nilsson, C, et al.
(författare)
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Circadian variation in human cerebrospinal fluid production measured by magnetic resonance imaging
- 1992
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Ingår i: American Journal of Physiology: Regulatory, Integrative and Comparative Physiology. - 1522-1490. ; 262:1, s. 20-24
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Tidskriftsartikel (refereegranskat)abstract
- Recent advances in magnetic resonance imaging have made it possible to visualize and quantify flow of cerebrospinal fluid (CSF) in the brain. The net flow of CSF through the cerebral aqueduct was used to measure CSF production in six normal volunteers at different times during a 24-h period. CSF production varied greatly both intra- and interindividually. The average CSF production in each time interval showed a clear tendency to circadian variation, with a minimum production 30% of maximum values (12 +/- 7 ml/h) approximately 1800 h and a nightly peak production approximately 0200 h of 42 +/- 2 ml/h. The total CSF production during the whole 24-h period, calculated as an average of all measurements, was 650 ml for the whole group and 630 ml for repeated measurements in each time interval in one of the volunteers.
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| 18. |
- Noborn, Fredrik, et al.
(författare)
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Subtyping of cardiac amyloidosis by mass spectrometry-based proteomics of endomyocardial biopsies.
- 2023
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Ingår i: Amyloid : the international journal of experimental and clinical investigation : the official journal of the International Society of Amyloidosis. - : Informa UK Limited. - 1350-6129 .- 1744-2818. ; 30:1, s. 96-108
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Tidskriftsartikel (refereegranskat)abstract
- Cardiac amyloidosis is a severe condition leading to restrictive cardiomyopathy and heart failure. Mass spectrometry-based methods for cardiac amyloid subtyping have become important diagnostic tools but are currently used only in a few reference laboratories. Such methods include laser-capture microdissection to ensure the specific analysis of amyloid deposits. Here we introduce a direct proteomics-based method for subtyping of cardiac amyloidosis.Endomyocardial biopsies were retrospectively analysed from fresh frozen material of 78 patients with cardiac amyloidosis and from 12 biopsies of unused donor heart explants. Cryostat sections were digested with trypsin and analysed with liquid chromatography - mass spectrometry, and data were evaluated by proteomic software.With a diagnostic threshold set to 70% for each of the four most common amyloid proteins affecting the heart (LC κ, LC λ, TTR and SAA), 65 of the cases (87%) could be diagnosed, and of these, 61 cases (94%) were in concordance with the original diagnoses. The specimens were also analysed for the summed intensities of the amyloid signature proteins (ApoE, ApoA-IV and SAP). The intensities were significantly higher (p<0.001) for all assigned cases compared with controls.Cardiac amyloidosis can be successfully subtyped without the prior enrichment of amyloid deposits with laser microdissection.
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| 19. |
- Oldfors Hedberg, Carola, 1969, et al.
(författare)
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A new early-onset neuromuscular disorder associated with kyphoscoliosis peptidase (KY) deficiency.
- 2016
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Ingår i: European journal of human genetics : EJHG. - : Springer Science and Business Media LLC. - 1476-5438 .- 1018-4813. ; 24:12, s. 1771-1777
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Tidskriftsartikel (refereegranskat)abstract
- We describe a new early-onset neuromuscular disorder due to a homozygous loss-of-function variant in the kyphoscoliosis peptidase gene (KY). A 7.5-year-old girl with walking difficulties from 2 years of age presented with generalized muscle weakness; mild contractures in the shoulders, hips and feet; cavus feet; and lordosis but no scoliosis. She had previously been operated with Achilles tendon elongation. Whole-body MRI showed atrophy and fatty infiltration in the calf muscles. Biopsy of the vastus lateralis muscle showed variability in fiber size, with some internalized nuclei and numerous very small fibers with variable expression of developmental myosin heavy chain isoforms. Some small fibers showed abnormal sarcomeres with thickened Z-discs and small nemaline rods. Whole-exome sequencing revealed a homozygous one-base deletion (c.1071delG, p.(Thr358Leufs*3)) in KY, predicted to result in a truncated protein. Analysis of an RNA panel showed that KY is predominantly expressed in skeletal muscle in humans. A recessive variant in the murine ortholog Ky was previously described in a spontaneously generated mouse mutant with kyphoscoliosis, which developed postnatally and was caused by dystrophy of postural muscles. The abnormal distribution of Xin and Ky-binding partner filamin C in the muscle fibers of our patient was highly similar to their altered localization in ky/ky mouse muscle fibers. We describe the first human case of disease associated with KY inactivation. As in the mouse model, the affected child showed a neuromuscular disorder - but in contrast, no kyphoscoliosis.
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| 20. |
- Oldfors Hedberg, Carola, 1969, et al.
(författare)
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COX deficiency and leukoencephalopathy due to a novel homozygous APOPT1/COA8 mutation
- 2020
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Ingår i: Neurology-Genetics. - : Ovid Technologies (Wolters Kluwer Health). - 2376-7839. ; 6:4
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Tidskriftsartikel (refereegranskat)abstract
- Objective To describe the long-term follow-up and pathogenesis in a child with leukoencephalopathy and cytochrome c oxidase (COX) deficiency due to a novel homozygous nonsense mutation in APOPT1/COA8. Methods The patient was clinically investigated at 3, 5, 9, and 25 years of age. Brain MRI, repeat muscle biopsies with biochemical, morphologic, and protein expression analyses were performed, and whole-genome sequencing was used for genetic analysis. Results Clinical investigation revealed dysarthria, dysphagia, and muscle weakness following pneumonia at age 3 years. There was clinical regression leading to severe loss of ambulation, speech, swallowing, hearing, and vision. The clinical course stabilized after 2.5 years and improved over time. The MRI pattern in the patient demonstrated cavitating leukoencephalopathy, and muscle mitochondrial investigations showed COX deficiency with loss of complex IV subunits and ultrastructural abnormalities. Genetic analysis revealed a novel homozygous mutation in the APOPT1/COA8 gene, c.310T>C; p.(Gln104*). Conclusions We describe a novel nonsense mutation in APOPT1/COA8 and provide additional experimental evidence for a COX assembly defect in human muscle causing the complex IV deficiency. The long-term outcome of the disease seems in general to be favorable, and the characteristic MRI pattern with cavitating leukoencephalopathy in combination with COX deficiency should prompt for testing of the APOPT1/COA8 gene.
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| 21. |
- Oldfors Hedberg, Carola, 1969, et al.
(författare)
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Respiratory chain dysfunction in perifascicular muscle fibres in patients with dermatomyositis is associated with mitochondrial DNA depletion
- 2022
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Ingår i: Neuropathology and Applied Neurobiology. - : Wiley. - 0305-1846 .- 1365-2990. ; 48:7
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Tidskriftsartikel (refereegranskat)abstract
- Aims Patients with dermatomyositis (DM) suffer from reduced aerobic metabolism contributing to impaired muscle function, which has been linked to cytochrome c oxidase (COX) deficiency in muscle tissue. This mitochondrial respiratory chain dysfunction is typically seen in perifascicular regions, which also show the most intense inflammatory reaction along with capillary loss and muscle fibre atrophy. The objective of this study was to investigate the pathobiology of the oxidative phosphorylation deficiency in DM. Methods Muscle biopsy specimens with perifascicular COX deficiency from five juveniles and seven adults with DM were investigated. We combined immunohistochemical analyses of subunits in the respiratory chain including complex I (subunit NDUFB8), complex II (succinate dehydrogenase, subunit SDHB) and complex IV (COX, subunit MTCO1) with in situ hybridisation, next generation deep sequencing and quantitative polymerase chain reaction (PCR). Results There was a profound deficiency of complexes I and IV in the perifascicular regions with enzyme histochemical COX deficiency, whereas succinate dehydrogenase activity and complex II were preserved. In situ hybridisation of mitochondrial RNA showed depletion of mitochondrial DNA (mtDNA) transcripts in the perifascicular regions. Analysis of mtDNA by next generation deep sequencing and quantitative PCR in affected muscle regions showed an overall reduction of mtDNA copy number particularly in the perifascicular regions. Conclusion The respiratory chain dysfunction in DM muscle is associated with mtDNA depletion causing deficiency of complexes I and IV, which are partially encoded by mtDNA, whereas complex II, which is entirely encoded by nuclear DNA, is preserved. The depletion of mtDNA indicates a perturbed replication of mtDNA explaining the muscle pathology and the disturbed aerobic metabolism.
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| 22. |
- Omar, Omar, et al.
(författare)
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Barrier membranes: More than the barrier effect?
- 2019
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Ingår i: Journal of Clinical Periodontology. - : Wiley. - 0303-6979. ; 46:S21, s. 103-123
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Tidskriftsartikel (refereegranskat)abstract
- Aim To review the knowledge on the mechanisms controlling membrane-host interactions in guided bone regeneration (GBR) and investigate the possible role of GBR membranes as bioactive compartments in addition to their established role as barriers. Materials and Methods A narrative review was utilized based on in vitro, in vivo and available clinical studies on the cellular and molecular mechanisms underlying GBR and the possible bioactive role of membranes. Results Emerging data demonstrate that the membrane contributes bioactively to the regeneration of underlying defects. The cellular and molecular activities in the membrane are intimately linked to the promoted bone regeneration in the underlying defect. Along with the native bioactivity of GBR membranes, incorporating growth factors and cells in membranes or with graft materials may augment the regenerative processes in underlying defects. Conclusion In parallel with its barrier function, the membrane plays an active role in hosting and modulating the molecular activities of the membrane-associated cells during GBR. The biological events in the membrane are linked to the bone regenerative and remodelling processes in the underlying defect. Furthermore, the bone-promoting environments in the two compartments can likely be boosted by strategies targeting both material aspects of the membrane and host tissue responses.
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| 23. |
- Roos, Sara, 1979, et al.
(författare)
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Mitochondrial complex IV deficiency caused by a novel frameshift variant in MT-CO2 associated with myopathy and perturbed acylcarnitine profile
- 2019
-
Ingår i: European Journal of Human Genetics. - : Springer Science and Business Media LLC. - 1018-4813 .- 1476-5438. ; 27:2, s. 331-335
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Tidskriftsartikel (refereegranskat)abstract
- Mitochondrial myopathies are a heterogeneous group of disorders associated with a wide range of clinical phenotypes. We present a 16-year-old girl with a history of exercise intolerance since childhood. Acylcarnitine species suggestive of multiple acyl-CoA dehydrogenase deficiency were found in serum, however genetic analysis did not reveal variants in genes associated with this disorder. Biochemical analyses of skeletal muscle mitochondria revealed an isolated and extremely low activity of cytochrome c oxidase (COX). This finding was confirmed by enzyme histochemistry, which demonstrated an almost complete absence of fibers with normal COX activity. Whole-exome sequencing revealed a single base-pair deletion (m.8088delT) in MT-CO2, which encodes subunit 2 of COX, resulting in a premature stop codon. Restriction fragment length polymorphism-analysis confirmed mtDNA heteroplasmy with high mutant load in skeletal muscle, the only clinically affected tissue, but low levels in other investigated tissues. Single muscle fiber analysis showed segregation of the mutant genotype with respiratory chain dysfunction. Immuno-histochemical studies indicated that the truncating variant in COX2 has an inhibitory effect on the assembly of the COX holoenzyme.
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| 24. |
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| 25. |
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| 26. |
- Sayardoust, Shariel, et al.
(författare)
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Implant survival and marginal bone loss at turned and oxidized implants in periodontitis-susceptible smokers and never-smokers : A retrospective, clinical, radiographic case-control study
- 2013
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Ingår i: Journal of Periodontology. - : John Wiley & Sons. - 0022-3492 .- 1943-3670. ; 84:12, s. 1775-1782
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Tidskriftsartikel (refereegranskat)abstract
- Background: Little is known about the long-term outcome of oxidized surface oral implants, especially in periodontitis-susceptible smokers. The aim of this study is to determine implant survival and marginal bone loss at turned and oxidized implants in smokers and never-smokers with periodontitis.Methods: Forty smokers and 40 never-smokers with experience of advanced periodontal disease, treated with implants 5 years previously, are included in this study. Groups were matched for sex, oral hygiene, and implant distribution, and patients were subgrouped by implant surface type (turned or oxidized).Results: The overall implant survival rate was 96.9% in never-smokers and 89.6% in smokers. Compared with oxidized implants, turned implants failed more frequently in smokers. In smokers, mean (standard error of the mean) marginal bone loss at 5 years was 1.54 (0.21) mm at turned and 1.16 (0.24) mm at oxidized implants. In never-smokers, significantly greater bone loss was found at oxidized implants, 1.26 (0.15) mm, than at turned implants, 0.84 (0.14) mm. Oxidized implants demonstrated similar bone loss for both groups. Turned implants lost significantly more bone in smokers. Compared with never-smokers, the smokers' likelihood ratio for implant failure was 4.68, 6.40 for turned and 0.00 for oxidized implants.Conclusions: The results of the study underscore the need for prevention and cessation of smoking. Turned implants failed more frequently and lost more marginal bone in smokers. In contrast, oxidized implants showed similar failure rates and bone loss in smokers and never-smokers. Turned implants displayed less bone loss than oxidized implants in never-smokers. Oxidized surface implants are more suitable for patients susceptible to periodontitis who smoke.
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| 27. |
- Shaheen, S., et al.
(författare)
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The relation between paracetamol use and asthma : a GA2LEN European case-control study
- 2008
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Ingår i: European Respiratory Journal. - : European Respiratory Society (ERS). - 0903-1936 .- 1399-3003. ; 32:5, s. 1231-1236
-
Tidskriftsartikel (refereegranskat)abstract
- Studies from the UK and USA suggest that frequent use of paracetamol (acetaminophen) may increase the risk of asthma, but data across Europe are lacking. As part of a multicentric case-control study organised by the Global Allergy and Asthma European Network (GA(2)LEN), it was examined whether or not frequent paracetamol use is associated with adult asthma across Europe. The network compared 521 cases with a diagnosis of asthma and reporting of asthma symptoms within the last 12 months with 507 controls with no diagnosis of asthma and no asthmatic symptoms within the last 12 months across 12 European centres. All cases and controls were selected from the same population, defined by age (20-45 yrs) and place of residence. In a random effects meta-analysis, weekly use of paracetamol, compared with less frequent use, was strongly positively associated with asthma after controlling for confounders. There was no evidence for heterogeneity across centres. No association was seen between use of other analgesics and asthma. These data add to the increasing and consistent epidemiological evidence implicating frequent paracetamol use in asthma in diverse populations.
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| 28. |
- Slotte, Christer, 1954, et al.
(författare)
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Gene Expression of Inflammation and Bone Healing in Peri-Implant Crevicular Fluid after Placement and Loading of Dental Implants. A Kinetic Clinical Pilot Study Using Quantitative Real-Time PCR.
- 2012
-
Ingår i: Clinical implant dentistry and related research. - : Wiley. - 1708-8208 .- 1523-0899. ; 14:5, s. 723-736
-
Tidskriftsartikel (refereegranskat)abstract
- Purpose: Early detection of healing complications after placement of dental implants is a pressing but elusive goal. This paper proposes a non-invasive diagnostic tool for monitoring healing- and peri-implant disease specific genes, complementary to clinical evaluations. Material and Methods: Eighteen partially edentulous patients were recruited to this pilot study. Three Brånemark TiUnite® implants/patient (Nobel Biocare) were placed in a one-stage procedure. Abutments with smooth or rough (TiUnite®) surface were placed. The test group (n=9) received fixed bridges (immediate loading), whereas the control group (n=9) implants were loaded 3 months after surgery. In addition to clinical measurements, crevicular fluid was collected using paper strips at the implant abutments 2, 14, 28, and 90 days postoperative. mRNA was extracted, purified, and converted to cDNA. Quantitative PCR assays for IL-1β, TNF-α, Osteocalcin (OC), Alkaline Phosphatase (ALP), Cathepsin K, Tartrate Resistant Acid Phosphatase, and 18S ribosomal RNA were designed and validated. Relative gene expression levels were calculated. Results: One implant was lost in the control group and three in the test group. In one test patient, one implant showed lowered stability after 2 to 4 weeks and was unloaded. Later implant stability improved which allowed for loading after 3 to 4 months. TNF-α and ALP most commonly showed correlation with clinical parameters followed by IL-1β and OC. The strongest correlation was found for TNF-α with clinical complications at 2 and 14 days (p=.01/r=-048, and p=.0004/r=-0.56, respectively; test and control groups together). In some cases, gene expression predicted clinical complications (TNF-α, ALP, CK). Conclusion: This study is based on samples from few individuals; still, some genes showed correlation with clinical findings. Further studies are needed to refine and optimize the sampling process, to find the appropriate panel, and to validate gene expression for monitoring implant healing.
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| 29. |
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| 30. |
- Sofou, Kalliopi, et al.
(författare)
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Prenatal onset of mitochondrial disease is associated with sideroflexin 4 deficiency
- 2019
-
Ingår i: Mitochondrion. - : Elsevier BV. - 1567-7249. ; 47, s. 76-81
-
Tidskriftsartikel (refereegranskat)abstract
- Prenatal onset of mitochondrial disease has been described in two cases with recessive mutations in the sideroflexin 4 gene (SFXN4). We present a third case with complex I deficiency associated with novel mutations in SFXN4. Our patient presented with intrauterine growth retardation, neonatal lactic acidosis, and developed macrocytic anemia and optic nerve hypoplasia. Muscle mitochondrial investigations revealed ultrastructural abnormalities, severe deficiency of complex I enzyme activity, and loss of subunit proteins. Whole-exome sequencing revealed bi-allelic SFXN4 mutations: a 1-base deletion, c.969delG, leading to frameshift and a premature stop codon, p.(G1n323Hisfs*20), and a stop-loss mutation in the C-terminal region, c.1012 T > C; p. (*388Glnext2), resulting in elongation of the protein by two amino acids. Expression analysis of mRNA from muscle showed loss of SFXN4 transcripts.
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| 31. |
- Stenberg, Johan A., et al.
(författare)
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Pest risk assessment of selected Epitrix species : Scientific Opinion of the Panel on Plant Health of the Norwegian Scientific Committee for Food and Environment
- 2019
-
Rapport (övrigt vetenskapligt/konstnärligt)abstract
- Epitrix is a taxonomically complex genus, with 162 described species all over the world, and most likely many more undescribed species. Due to taxonomic difficulties identifying the species, there is considerable uncertainty regarding which species that feed on cultivated crops. At least 13 Epitrix species are known to damage the tubers of potato, which is the crop of concern in northern Europe. At least five of those Epitrix species (E. hirtipennis, E. fasciata, E.cucumeris, E. papa and E. pubescens) have established themselves outside their native range, spurring concerns that they may spread further and potentially cause damage in new areas where potato is cultivated. It is unknown how most of these species have moved from country to country, but there have been several interceptions of unknown Epitrix species in shipments of ware potatoes.
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| 32. |
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| 33. |
- Stenberg, Johan A., et al.
(författare)
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Risk assessment of the biological control product Atheta-System with the organism Atheta coriaria Kraatz : Scientific Opinion of the Panel on Plant Health of the Norwegian Scientific Committee for Food and Environment
- 2020
-
Rapport (övrigt vetenskapligt/konstnärligt)abstract
- Atheta-System with the rove beetle Atheta coriaria (Kraatz 1856) as the active organism is sought to be used as a biocontrol agent for augmentation biological control in Norway. Atheta-System is intended for use against soil dwelling stages of fungus gnats (e.g. Bradysiapaupera), shore flies (Scatella stagnalis), and thrips (e.g. Frankliniella occidentallis) in greenhouses, plastic tunnels, and other closed or controlled climate cultivations of horticultural crops, incl. soft-fruit crops, vegetables, ornamentals, and kitchen herbs.
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| 34. |
- Ståhlberg, Anders, 1975, et al.
(författare)
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Normal and Functional TP53 in Genetically Stable Myxoid/Round Cell Liposarcoma
- 2014
-
Ingår i: Plos One. - : Public Library of Science (PLoS). - 1932-6203. ; 9:11
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Tidskriftsartikel (refereegranskat)abstract
- Myxoid/round-cell liposarcoma (MLS/RCLS) is characterized by either the fusion gene FUS-DDIT3 or the less commonly occurring EWSR1-DDIT3 and most cases carry few or no additional cytogenetic changes. There are conflicting reports concerning the status and role of TP53 in MLS/RCLS. Here we analysed four MLS/RCLS derived cell lines for TP53 mutations, expression and function. Three SV40 transformed cell lines expressed normal TP53 proteins. Irradiation caused normal posttranslational modifications of TP53 and induced P21 expression in two of these cell lines. Transfection experiments showed that the FUS-DDIT3 fusion protein had no effects on irradiation induced TP53 responses. Ion Torrent AmpliSeq screening, using the Cancer Hotspot panel, showed no dysfunctional or disease associated alleles/mutations. In conclusion, our results suggest that most MLS/RCLS cases carry functional TP53 genes and this is consistent with the low numbers of secondary mutations observed in this tumor entity.
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| 35. |
- Ståhlberg, Anders, 1975, et al.
(författare)
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Quantitative PCR Analysis of DNA, RNAs, and Proteins in the Same Single Cell.
- 2012
-
Ingår i: Clinical chemistry. - : Oxford University Press (OUP). - 1530-8561 .- 0009-9147. ; 58:12, s. 1682-91
-
Tidskriftsartikel (refereegranskat)abstract
- The single cell represents the basic unit of all organisms. Most investigations have been performed on large cell populations, but understanding cell dynamics and heterogeneity requires single-cell analysis. Current methods for single-cell analysis generally can detect only one class of analytes.
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| 36. |
- Svec, David, et al.
(författare)
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Identification of inhibitors regulating cell proliferation and FUS-DDIT3 expression in myxoid liposarcoma using combined DNA, mRNA, and protein analyses.
- 2018
-
Ingår i: Laboratory investigation; a journal of technical methods and pathology. - : Elsevier BV. - 1530-0307. ; 98, s. 957-967
-
Tidskriftsartikel (refereegranskat)abstract
- FUS-DDIT3 belongs to the FET (FUS, EWSR1, and TAF15) family of fusion oncogenes, which collectively are considered to be key players in tumor development. Even though over 90% of all myxoid liposarcomas (MLS) have a FUS-DDIT3 gene fusion, there is limited understanding of the signaling pathways that regulate its expression. In order to study cell proliferation and FUS-DDIT3 regulation at mRNA and protein levels, we first developed a direct cell lysis approach that allows DNA, mRNA, and protein to be analyzed in the same sample using quantitative PCR, reverse transcription quantitative qPCR and proximity ligation assay, respectively. We screened 70 well-characterized kinase inhibitors and determined their effects on cell proliferation and expression of FUS-DDIT3 and FUS at both mRNA and protein levels in the MLS 402-91 cell line, where twelve selected inhibitors were evaluated further in two additional MLS cell lines. Both FUS-DDIT3 and FUS mRNA expression correlated with cell proliferation and both transcripts were co-regulated in most conditions, indicating that the common 5' FUS promotor is important in transcriptional regulation. In contrast, FUS-DDIT3 and FUS protein levels displayed more cell line dependent expression. Furthermore, most JAK inhibitors caused FUS-DDIT3 downregulation at both mRNA and protein levels. In conclusion, defining factors that regulate FUS-DDIT3 expression opens new means to understand MLS development at the molecular level.
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| 37. |
- Svensson, Åse, et al.
(författare)
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ARTISTS - Arterial streets for people : Guidance for planners and decision makers when reconstructing arterial streets.
- 2004
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Rapport (övrigt vetenskapligt/konstnärligt)abstract
- Conventional guidance on the design and management of urban roads and streets has tended to focus on either arterial roads or local access streets. There is currently a lack of a clear, consistent approach to the design of arterial streets, which combine both significant through traffic and urban place functions. This report aims to address this gap, by setting out an approach to the design and management of arterial streets - from a people-oriented perspective. This means that:• As users of the street, people – rather than vehicles - are taken as the startingpoint for the analysis and redesign of street-space; and• As local stakeholders, people are taken into account and included in the design and management process.In addressing people’s use of streets for a diversity of urban functions – and not just motor traffic movement - the aim is to achieve streets that offer a more positive contribution to sustainability, in all its economic, social and environmental dimensions.This report encourages new ways of thinking about how arterial streets areconceptualised, designed and managed, as part of the overall street system. This requires a rethinking of how the various functions of the arterial street are reconciled and provided for; and involves addressing the processes by which street-space is allocated, the ways in which design options are generated, and how options are selected for implementation.A series of ways of addressing the ‘arterial streets for people’ theme arerecommended, including:• Recognising that arterial streets satisfy the needs of both ‘through users’ and‘locale users’;• Developing a functional classification of street sections based on twoindependent dimensions: ‘link status’ and ‘place status’;• Incorporating public participation at each stage of the redesign process,including contributions to functional classification, visioning, generatingdesigns, and option selection; and• Suggesting a process for problem identification, objective setting, optiongeneration and assessment.The guidance in this report is based on experience and research from the European Commission project ARTISTS (Arterial Streets Towards Sustainability). This project has drawn on a series of street case studies in seven European countries, as well as learning from research and practice elsewhere.The report is aimed primarily at city authorities and other policy makers, practitioners and consultants with responsibility for the design and management of streets. It gives general guidance on concepts and techniques, which may be adapted to fit the relevant national or city context.
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| 38. |
- Svensson, Åse, et al.
(författare)
-
ARTISTS - huvudgator för alla : Vägledning för planerare och beslutsfattare vid utformning och ombyggnad av huvudgator
- 2004
-
Rapport (övrigt vetenskapligt/konstnärligt)abstract
- Konventionella guider för utformning och förvaltning av trafikleder och stadsgator har vanligtvis inriktats antingen mot huvudtrafikleder eller mot lokala stadsgator. Det är för närvarande brist på ett tydligt och konsekvent angreppssätt för arbetet med utformning av huvudgator där signifikant genomfartstrafik och lokala funktioner kombineras. Målet är att denna rapport ska avhjälpa den bristen genom att presentera riktlinjer för utformning och förvaltning av huvudgator – med människan i fokus. Det innebär att:• Människor – istället för bilar – skall ses som gatans användare och ärutgångspunkt för analys och ombyggnad av gaturummet• Hänsyn tas till medborgarna och de engageras i utformnings- ochförvaltningsprocessenGenom att ta hänsyn till att människan använder gatan för en mängd aktiviteter – och inte bara för att kunna förflytta sig med motorfordon – vill man åstadkomma gator som erbjuder ett positivt bidrag till en hållbar utveckling, i alla dess ekonomiska, sociala och miljöbetingade dimensioner.Denna rapport uppmuntrar till nya tankesätt för hur huvudgator konceptualiseras, utformas och förvaltas som en del av det övergripande gatunätet. För detta krävs en omprövning av hur huvudgatans olika funktioner skall förenas och tillhandahållas. Det kräver ett erkännande av huvudgatans olika funktioner och omprövning av hur dessa olika funktioner ska tillgodoses. Därför inriktar man sig på den process i vilken gatuutrymmet fördelas, på metoderna som används för att ta fram utformningsalternativ och på hur man väljer ut det alternativ som ska genomföras.En rad sätt att arbeta med området ”huvudgator med människan i fokus”rekommenderas, däribland:• Var uppmärksam på att huvudgator tillgodoser behov för både”genomfartsanvändare” och ”lokala användare”• Utveckla en funktionsbeskrivning genom klassificering av gatusektionerbaserad på två oberoende dimensioner: ”länk status” och ”plats status”• Föreslå en process som skall identifiera problemen, sätta upp mål, ta framalternativ och bedöma dem• Inkludera allmänheten i varje steg i processen, däribland i funktionsbeskrivningen av gatan, visionsskapande, utformning och val av alternativ.Riktlinjerna i denna rapport baseras på erfarenheter och forskning från EU-projektet ARTISTS (Arterial Streets Towards Sustainability). Detta projekt stödjer sig på ett antal fallstudier av gator i sju europeiska länder såväl som på forskning och praktisk erfarenhet. Den här rapporten riktar sig främst till myndigheter och andra beslutsfattare, praktiker och konsulter med ansvar för utformning och förvaltning av gator. Den ger generella riktlinjer för koncept och tekniker som kan anpassas till varje lands eller stads specifika förutsättningar.
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| 39. |
- Thomsen, Christer, et al.
(författare)
-
A conserved N-terminal motif is required for complex formation between FUS, EWSR1, TAF15 and their oncogenic fusion proteins.
- 2013
-
Ingår i: FASEB journal : official publication of the Federation of American Societies for Experimental Biology. - : Wiley. - 1530-6860. ; 27:12, s. 4965-74
-
Tidskriftsartikel (refereegranskat)abstract
- The three FET (FUS, EWSR1, and TAF15) family RNA binding proteins are expressed in all tissues and almost all cell types. The disordered N-terminal parts are always present in FET fusion oncoproteins of sarcomas and leukemia. Mutations in FUS and TAF15 cause aggregation of FET proteins in neurological disorders. Here we used recombinant proteins in pulldown experiments and mass spectrometry to identify major interaction partners of the FET N-terminal parts. We report that FUS, EWSR1, and TAF15 form homo- and heterocomplexes as major binding partners and identify an evolutionarily conserved N-terminal motif (FETBM1) that is required for this interaction. The binding is RNA and DNA independent and robust up to 1 M of NaCl. The localization of FETBM1 and its target sequences supports a simple model for FET protein aggregation as reported in neurological disorders such as amyotrophic lateral sclerosis, frontotemporal dementia, and essential tremor. The FETBM1 localization also explains the binding of normal full-length FET proteins to their oncogenic fusion proteins.-Thomsen, C., Grundevik, P., Elias, P., Ståhlberg, A., Åman, P. A conserved N-terminal motif is required for complex formation between FUS, EWSR1, TAF15 and their oncogenic fusion proteins.
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| 40. |
- Thomsen, Christer, et al.
(författare)
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Fused in sarcoma (FUS) interacts with the cytolinker protein plectin: implications for FUS subcellular localization and function.
- 2012
-
Ingår i: Experimental cell research. - : Elsevier BV. - 1090-2422 .- 0014-4827. ; 318:5, s. 653-61
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Tidskriftsartikel (refereegranskat)abstract
- Fused in sarcoma (FUS) is a multifunctional protein involved in transcriptional control, pre-mRNA processing, RNA transport and translation. The domain structure of FUS reflects its functions in gene regulation and its ability to interact with other proteins, RNA and DNA. By use of a recombinant fragment of FUS in pull-down experiments followed by mass spectrometry analysis we have identified a novel interaction between the FUS N-terminal and the cytolinker plectin. An in situ proximity ligation assay confirmed that FUS-plectin interactions take place in the cytoplasm of cells. Furthermore, plectin deficient cells showed an altered subcellular localization of FUS and a deregulated expression of mRNAs bound to FUS. Our results show that plectin is important for normal FUS localization and function. Mutations involving FUS are causative factors in sarcomas and leukemias and also hereditary forms of amyotrophic lateral sclerosis and frontotemporal lobar degeneration. Plectin deficiency causes epidermolysis bullosa, a disease involving the skin and neuromuscular system. The novel FUS-plectin interaction offers new perspectives for understanding the role of FUS and plectin mutations in the pathogenesis of these diseases.
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| 41. |
- Thomsen, Christer
(författare)
-
Molecular analysis of the FET family fusion oncoprotein FUS-DDIT3
- 2012
-
Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Chromosomal translocations leading to formation of tumor type specific fusion oncogenes are frequently found in human cancers. The FET family genes (FUS, EWSR1 and TAF15) occur in translocations with genes encoding various transcription factors in sarcomas and leukemias. The resultant fusion genes encode chimeric protein products containing the N-terminal domain (NTD) of a FET family protein juxtaposed to the DNA binding domain of a transcription factor. The constitutively expressed fusion proteins act as abnormal transcription factors and are considered to be the primary initiating and driving factors of tumorigenesis. Myxoid liposarcoma (MLS) is defined by the t(12;16)(q13;p11) that cause the fusion of the FUS and DDIT3 genes and expression of a chimeric FUS-DDIT3 oncoprotein. The aim of this thesis was to functionally characterize the FUS-DDIT3 fusion oncoprotein and the normal FUS, EWS, TAF15 and DDIT3 counterparts. To understand the involvement of DDIT3 in cancer and other pathologies we defined the genes and cellular functions it regulates. We observed that DDIT3 may localize to both the cell cytoplasm and nucleus. Microarray analysis revealed that cytoplasmic or nuclear DDIT3 regulate distinct sets of target genes. However, cytoplasmic or nuclear DDIT3 control the same cellular functions of which cell migration, proliferation, apoptosis/survival and cell cycle were most clearly affected. The majority of target genes were repressed supporting a role for DDIT3 as a dominant negative factor that may sequester and block the action of cytoplasmic and nuclear transcription factors. Subcellular localization is likely to be an important regulatory mechanism for control of DDIT3 activity. We further studied the molecular function of the FUS, EWS and TAF15 N-terminal domains with focus on their involvement in protein-protein interactions. The NTDs of FET proteins were found to bind the cytolinker plectin and FUS was shown to form complexes with plectin in the cell cytoplasm. Plectin expression was required for normal FUS function as plectin knockout cells revealed a shift in FUS nucleo-cytoplasmic distribution and a deregulation of FUS function in gene expression. Furthermore, we identified a conserved motif of the FUS, EWS and TAF15 NTDs that mediates interaction with full-length FET family proteins. The NTD of the FUS-DDIT3 fusion oncoprotein retained the capacity to bind wildtype FET proteins and disrupt their normal nuclear localization pattern. We also observed an involvement of wildtype FUS in the regulation of FUS-DDIT3 target genes. Finally, several components of the human SWI/SNF complex were isolated by pull-down with the FUS NTD. The SWI/SNF subunits Brg1 and ARID1A were further confirmed to form complexes with FUS-DDIT3 as well as wildtype FUS in the nuclei of MLS cells. SWI/SNF complexes control gene expression by modulating nucleosome positioning and are key players in cellular differentiation processes. Aberrant activity of SWI/SNF has further been linked with development of various cancers. Interaction with SWI/SNF is thus likely to be important for the impact of FUS-DDIT3 on gene regulation, differentiation processes and the transformed state of MLS.
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| 42. |
- Thomsen, Christer, 1977, et al.
(författare)
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Proteomic characterisation of polyglucosan bodies in skeletal muscle in RBCK1 deficiency
- 2022
-
Ingår i: Neuropathology and Applied Neurobiology. - : Wiley. - 0305-1846 .- 1365-2990. ; 48:1
-
Tidskriftsartikel (refereegranskat)abstract
- Aims Several neurodegenerative and neuromuscular disorders are characterised by storage of polyglucosan, consisting of proteins and amylopectin-like polysaccharides, which are less branched than in normal glycogen. Such diseases include Lafora disease, branching enzyme deficiency, glycogenin-1 deficiency, polyglucosan body myopathy type 1 (PGBM1) due to RBCK1 deficiency and others. The protein composition of polyglucosan bodies is largely unknown. Methods We combined quantitative mass spectrometry, immunohistochemical and western blot analyses to identify the principal protein components of polyglucosan bodies in PGBM1. Histologically stained tissue sections of skeletal muscle from four patients were used to isolate polyglucosan deposits and control regions by laser microdissection. Prior to mass spectrometry, samples were labelled with tandem mass tags that enable quantitative comparison and multiplexed analysis of dissected samples. To study the distribution and expression of the accumulated proteins, immunohistochemical and western blot analyses were performed. Results Accumulated proteins were mainly components of glycogen metabolism and protein quality control pathways. The majority of fibres showed depletion of glycogen and redistribution of key enzymes of glycogen metabolism to the polyglucosan bodies. The polyglucosan bodies also showed accumulation of proteins involved in the ubiquitin-proteasome and autophagocytosis systems and protein chaperones. Conclusions The sequestration of key enzymes of glycogen metabolism to the polyglucosan bodies may explain the glycogen depletion in the fibres and muscle function impairment. The accumulation of components of the protein quality control systems and other proteins frequently found in protein aggregate disorders indicates that protein aggregation may be an essential part of the pathobiology of polyglucosan storage.
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| 43. |
- Turri, Alberto, 1973, et al.
(författare)
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Guided bone regeneration is promoted by the molecular events in the membrane compartment.
- 2016
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Ingår i: Biomaterials. - : Elsevier BV. - 1878-5905 .- 0142-9612. ; 84, s. 167-183
-
Tidskriftsartikel (refereegranskat)abstract
- The working hypothesis of guided bone regeneration (GBR) is that the membrane physically excludes non-osteogenic tissues from interfering with bone healing. However, the underlying mechanisms are insufficiently explained. This study aimed to investigate the molecular and structural pattern of bone healing in trabecular bone defects, with and without naturally derived resorbable membrane. Defects were created in rat femurs and treated with the membrane or left empty (sham). After 3d, 6d and 28d, the defect sites and membranes were harvested and analyzed with histology, histomorphometry, quantitative-polymerase chain reaction (qPCR), Western blot (WB) and immunohistochemistry (IHC). Histomorphometry demonstrated that the presence of the membrane promoted bone formation in early and late periods. This was in parallel with upregulation of cell recruitment and coupled bone remodeling genes in the defect. Cells recruited into the membrane expressed signals for bone regeneration (BMP-2, FGF-2, TGF-β1 and VEGF). Whereas the native membrane contained FGF-2 but not BMP-2, an accumulation of FGF-2 and BMP-2 proteins and immunoreactive cells were demonstrated by WB and IHC in the invivo implanted membrane. The results provide cellular and molecular evidence suggesting a novel role for the membrane during GBR, by acting as a bioactive compartment rather than a passive barrier.
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| 44. |
- Turri, Alberto, 1973, et al.
(författare)
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Modulation of gene expression and bone formation by expanded and dense polytetrafluoroethylene membranes during guided bone regeneration: An experimental study
- 2024
-
Ingår i: Clinical Implant Dentistry and Related Research. - 1523-0899. ; 26:2, s. 266-280
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Tidskriftsartikel (refereegranskat)abstract
- BackgroundNonresorbable membranes promote bone formation during guided bone regeneration (GBR), yet the relationships between membrane properties and molecular changes in the surrounding tissue are largely unknown. AimTo compare the molecular events in the overlying soft tissue, the membrane, and the underlying bone defect during GBR using dual-layered expanded membranes versus dense polytetrafluoroethylene (PTFE) membranes. Materials and MethodsRat femur defects were treated with either dense PTFE (d-PTFE) or dual-layered expanded PTFE (dual e-PTFE) or left untreated as a sham. Samples were collected after 6 and 28 days for gene expression, histology, and histomorphometry analyses. ResultsThe two membranes promoted the overall bone formation compared to sham. Defects treated with dual e-PTFE exhibited a significantly higher proportion of new bone in the top central region after 28 days. Compared to that in the sham, the soft tissue in the dual e-PTFE group showed 2-fold higher expression of genes related to regeneration (FGF-2 and FOXO1) and vascularization (VEGF). Furthermore, compared to cells in the d-PTFE group, cells in the dual e-PTFE showed 2.5-fold higher expression of genes related to osteogenic differentiation (BMP-2), regeneration (FGF-2 and COL1A1), and vascularization (VEGF), in parallel with lower expression of proinflammatory cytokines (IL-6 and TNF-& alpha;). Multiple correlations were found between the molecular activities in membrane-adherent cells and those in the soft tissue. ConclusionSelective surface modification of the two sides of the e-PTFE membrane constitutes a novel means of modulating the tissue response and promoting bone regeneration.
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| 45. |
- Visuttijai, Kittichate, et al.
(författare)
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Glycogenin is dispensable for glycogen synthesis in human muscle and glycogenin deficiency causes polyglucosan storage.
- 2020
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Ingår i: The Journal of clinical endocrinology and metabolism. - : The Endocrine Society. - 1945-7197 .- 0021-972X. ; 105:2, s. 557-566
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Tidskriftsartikel (refereegranskat)abstract
- To investigate the importance of glycogenin-1 and glycogenin-2 for glycogen synthesis in skeletal and cardiac muscle.Glycogenin-1 and glycogenin-2 expression was analyzed by western blot, mass spectrometry, and immunohistochemistry in liver, heart, and skeletal muscle from controls and in skeletal and cardiac muscle from patients with glycogenin-1 deficiency.Both glycogenin-1 and glycogenin-2 were found to be expressed in liver, but only glycogenin-1 was identified in heart and skeletal muscle from controls. In patients with truncating GYG1 mutations, neither glycogenin-1 nor glycogenin-2 was expressed in skeletal muscle. However, non-functional glycogenin-1 but not glycogenin-2 was identified in cardiac muscle from patients with cardiomyopathy due to GYG1 missense mutations. By immunohistochemistry, the mutated glycogenin-1 co-localized with the storage of glycogen and polyglucosan in cardiomyocytes.Glycogen can be synthesised in the absence of glycogenin, and glycogenin-1 deficiency is not compensated for by upregulation of functional glycogenin-2. Absence of glycogenin-1 leads to focal accumulation of glycogen and polyglucosan in skeletal muscle fibers. Expression of mutated glycogenin-1 in the heart is deleterious, and it leads to storage of abnormal glycogen and cardiomyopathy.
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| 46. |
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| 47. |
- Åman, Pierre, 1953, et al.
(författare)
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Regulatory mechanisms, expression levels and proliferation effects of the FUS-DDIT3 fusion oncogene in liposarcoma.
- 2016
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Ingår i: The Journal of pathology. - : Wiley. - 1096-9896 .- 0022-3417. ; 238:5, s. 689-99
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Tidskriftsartikel (refereegranskat)abstract
- Fusion oncogenes are among the most common types of oncogene in human cancers. The gene rearrangements result in new combinations of regulatory elements and functional protein domains. Here we studied a subgroup of sarcomas and leukaemias characterized by the FET (FUS, EWSR1, TAF15) family of fusion oncogenes, including FUS-DDIT3 in myxoid liposarcoma (MLS). We investigated the regulatory mechanisms, expression levels and effects of FUS-DDIT3 in detail. FUS-DDIT3 showed a lower expression than normal FUS at both the mRNA and protein levels, and single-cell analysis revealed a lack of correlation between FUS-DDIT3 and FUS expression. FUS-DDIT3 transcription was regulated by the FUS promotor, while its mRNA stability depended on the DDIT3 sequence. FUS-DDIT3 protein stability was regulated by protein interactions through the FUS part, rather than the leucine zipper containing DDIT3 part. In addition, in vitro as well as in vivo FUS-DDIT3 protein expression data displayed highly variable expression levels between individual MLS cells. Combined mRNA and protein analyses at the single-cell level showed that FUS-DDIT3 protein expression was inversely correlated to the expression of cell proliferation-associated genes. We concluded that FUS-DDIT3 is uniquely regulated at the transcriptional as well as the post-translational level and that its expression level is important for MLS tumour development. The FET fusion oncogenes are potentially powerful drug targets and detailed knowledge about their regulation and functions may help in the development of novel treatments. Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
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