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- Harandi, Vahid M., 1985-
(author)
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A Muscle Perspective on the Pathophysiology of Amyotrophic Lateral Sclerosis : Differences between extraocular and limb muscles
- 2016
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Doctoral thesis (other academic/artistic)abstract
- Background: Amyotrophic lateral sclerosis (ALS) is a late-onset progressive neurodegenerative disorder. ALS has been traditionally believed to be primarily a motor neuron disease. However, accumulating data indicate that loss of contact between the axons and the muscle fibres occurs early; long before the death of motor neurons and that muscle fibres may initiate motor neuron degeneration. Thus, the view of ALS is changing focus from motor neurons alone to also include the muscle fibres and the neuromuscular junctions (NMJs). While skeletal muscles are affected in ALS, oculomotor disturbances are not dominant features of this disease and extraocular muscles (EOMs) are far less affected than limb muscles. Why oculomotor neurons and EOMs are capable to be more resistant in the pathogenetic process of ALS is still unknown.The overall goal of this thesis is to explore the pathophysiology of ALS from a muscle perspective and in particular study the expression and distribution of key neurotrophic factors (NTFs) and Wnt proteins in EOMs and limb muscles from ALS donors and from SOD1G93A transgenic mice. Comparisons were made with age-matched controls to distinguish between changes related to ALS and to ageing.Results: Brain-derived neurotrophic factor (BDNF), glial cell line-derived neurotrophic factor (GDNF), neurotrophin-3 (NT-3) and neurotrophin-4/5 (NT-4) were present in EOMs and limb muscles at both mRNA and protein levels in control mice. The mRNA levels of BDNF, NT-3 and NT-4 were significantly lower in EOMs than in limb muscles of early and/or late control mice, indicating an intrinsic difference in NTFs expression between EOMs and limb muscles. qRT-PCR analysis showed significantly upregulated mRNA levels of NT-3 and GDNF in EOMs but significantly downregulated mRNA levels of NT-4 in limb muscles from SOD1G93A transgenic mice at early stage. The NTFs were detected immunohistochemically in NMJs, nerve axons and muscle fibres. The expression of BDNF, GDNF and NT-4 on NMJs of limb muscles, but not of EOMs, was significantly decreased in terminal stage ALS animals as compared to the limb muscles of the age-matched controls. In contrast, NTFs expression in intramuscular nerve axons did not present significant changes in either muscle group of early or late ALS mice. NTFs, especially BDNF and NT-4 were upregulated in some small-sized muscle fibres in limb muscles of late stage ALS mice. All the four Wnt isoforms, Wnt1, Wnt3a, Wnt5a and Wnt7a were detected in most axon profiles in all human EOMs with ALS, whereas significantly fewer axon profiles were positive in the human limb muscles except for Wnt5a. Similar differential patterns were found in myofibres, except for Wnt7a, where its expression was elevated within sarcolemma of limb muscle fibres. β-catenin, a marker of the canonical Wnt pathway was activated in a subset of myofibres in the EOMs and limb muscle in all ALS patients. In the SOD1G93A mouse, all four Wnt isoforms were significantly decreased in the NMJs at the terminal stage compared to age matched controls.Conclusions: There were clear differences in NTF and Wnt expression patterns between EOM and limb muscle, suggesting that they may play a role in the distinct susceptibility of these two muscle groups to ALS. In particular, the early upregulation of GDNF and NT-3 in the EOMs might play a role in the preservation of the EOMs in ALS. Further studies are needed to determine whether these proteins and the pathways they control may be have a future potential as protecting agents for other muscles.
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| 3. |
- Janbaz, Adrihan H., et al.
(author)
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Intermediate Filaments in the Human Extraocular Muscles
- 2014
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In: Investigative Ophthalmology and Visual Science. - : Association for Research in Vision and Ophthalmology (ARVO). - 0146-0404 .- 1552-5783. ; 55:8, s. 5151-5159
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Journal article (peer-reviewed)abstract
- PURPOSE.To investigate the distribution of the intermediate filament (IF) proteins desmin, vimentin, and nestin in human extraocular muscles (EOMs). METHODS. Healthy adult EOM samples were serially sectioned (5 and 1 mu m) and processed for immunohistochemistry, with specific antibodies (Abs) against desmin, vimentin, and nestin and different myosin heavy chains (MyHCs), including the newly characterized Ab MYH7b against MyHC slow tonic. The distribution of desmin was also studied in EOMs at 16 to 18 weeks of gestation.RESULTS.Desmin was present in the vast majority of muscle fibers. Notably, muscle fibers that contained MyHC slow tonic were either unlabeled or very weakly labeled with three different Abs against desmin. These muscle fibers had normal cytoarchitecture and intact basement membrane. In fetal muscle, desmin was also absent or weak in myotubes containing MyHC slow tonic. Nestin was detected in a large proportion of muscle fibers in the orbital layer and to some extent also in the global layer, whereas no muscle fibers contained vimentin. Desmin and nestin were enriched at neuromuscular junctions, as in limb muscle. In contrast, some myotendinous junctions lacked desmin or nestin.CONCLUSIONS.The human EOMs differed significantly from the other muscles in the body with respect to their IF composition. Desmin, hitherto regarded as a ubiquitous muscle cytoskeletal protein, was absent or only present in trace amounts in a subset of normal muscle fibers in adult and fetal EOMs. Nestin, normally downregulated early in the postnatal period, was present in a high proportion of adult muscle fibers.
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| 4. |
- Karlsson, Patrick, et al.
(author)
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Analysis of Skeletal Fibers in Three Dimensional Images : Methodological considerations
- 2007
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In: XXXVIth European Muscle Conference of the European Society for Muscle Research. ; , s. 130-
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Conference paper (other academic/artistic)abstract
- Knowledge of the detailed three dimensional organization of nuclei in skeletal muscle fibers is of fundamental importance for the understanding of the basic mechanisms involved in muscle wasting associated with for example neuromuscular disorders and aging. An ongoing interdisciplinary collaboration between the Centre for Image Analysis (CBA), and the Muscle Research Group (MRG), both at Uppsala University, addresses the issue of spatial distribution of myonuclei using confocal microscopic techniques together with advanced methods for computerized image analysis. Performing quantitative analysis on true three dimensional volume images captured by confocal microscopy gives us the option to perform in-depth statistical analysis of the relationship between neighboring myonuclei. The three dimensional representation enables extraction of a number of features for individual myonuclei, e.g., size and shape of a nucleus, and the myonuclear domain (in which each myonucleus control the gene products). This project investigates data sets from single muscle fibers sampled from mouse, rat, pig, human, horse and rhino to determine the myonuclei arrangement between species with a 100,000 fold difference in body weight. The appropriate image analysis tools needed for gaining the understanding of organization in three dimensional volume images are developed within the project to facilitate the analysis of similarities between species, and unique features within a species. The accumulated understanding of the spatial organization of myonuclei, and the effect of individual myonuclei size, will lead to an increased knowledge of basic mechanisms underlying muscle wasting in various neuromuscular disorders. This knowledge will hopefully lead to new therapeutic strategies that can be evaluated in experimental animal models prior to clinical testing trials in patients.
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| 6. |
- Monemi, M, et al.
(author)
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Myosin heavy chain composition of the human lateral pterygoid and digastric muscles in young adults and elderly.
- 2000
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In: Journal of Muscle Research and Cell Motility. - 0142-4319 .- 1573-2657. ; 21:4, s. 303-312
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Journal article (peer-reviewed)abstract
- The myosin heavy chain (MyHC) content in different parts of, two jaw opening muscle, the human lateral pterygoid and the digastric muscles of five young adult and five elderly subjects (mean age 22 and 73 years, respectively) was determined, using gel electrophoresis and immunohistochemical methods. The lateral pterygoid of both young and elderly contained predominantly slow MyHC, and fast A MyHC was the major fast isoform. In contrast, the digastric was composed of slow, fast A and fast X MyHCs in about equal proportions in both age groups. About half of the lateral pterygoid fibres contained mixtures of slow and fast MyHCs, often together with alpha-cardiac MyHC. In the digastric, co-existence of slow and fast MyHCs was rare, and alpha-cardiac MyHC was lacking. On the other hand, co-expression of fast A and fast X MyHCs was found more often in the digastric than in the lateral pterygoid. In both age groups about half of the digastric IIB fibres contained solely fast X MyHC. In the lateral pterygoid, type IIB fibres with pure fast X MyHC was found in only one subject. The lateral pterygoid in elderly showed a significant amount of fibres with solely fast A MyHC, which were occasionally found in young adults. In the digastric, no significant differences were found between young and elderly, although the muscles of elderly contained lower mean value of slow MyHC, as compared to that of young muscles. It is concluded that the lateral pterygoid and the digastric muscles differ not only in the MyHC composition but also in modifications of the MyHC phenotypes during aging, suggesting that they have separate roles in jaw opening function.
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| 7. |
- Yue, Jingxia, et al.
(author)
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Fatigue life prediction method of fairleads installed on a FPSO
- 2017
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In: Maritime Transportation and Harvesting of Sea Resources. - 9780815379935 ; 1, s. 679-687
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Conference paper (peer-reviewed)abstract
- As the key devices in the mooring system of a Floating Production Storage and Offloading vessel (FPSO), fairleads are used to guide the cables (wire rope or chain) from the vessel towards the anchor and help to change the vessel’s floating condition in a smooth manner. The fatigue strength of fairleads cannot be neglect-ed because the FPSO always suffers from complicated environmental loadings due to wave, current and wind; and induces highly varied loadings in the fairleads. In this paper, fatigue strength analysis is carried out for the fairleads of a FPSO served in the South Sea in China. Hydrodynamic performance of the FPSO cou-pling with its mooring system is firstly obtained, and then the short-term history of cable tension can be ob-tained by wave scatter diagram. The cable tension is regarded as the dynamic loading acted on the fairleads; and the corresponding history of stress range in the fairleads can be obtained by finite element analysis (FEA). At last, fatigue accumulating damage in the fairleads is calculated based on the rain-flow counting method and S-N curves. The estimation framework based on the ship motion and mooring tension coupling analysis in time domain proposed in this work can provide a fast fatigue life prediction of the fairleads when the ship is operated in different conditions.
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