| 1. |
- Abramsson, Alexandra, 1973, et al.
(författare)
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The zebrafish amyloid precursor protein-b is required for motor neuron guidance and synapse formation.
- 2013
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Ingår i: Developmental biology. - : Elsevier BV. - 1095-564X .- 0012-1606. ; 381:2, s. 377-88
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Tidskriftsartikel (refereegranskat)abstract
- The amyloid precursor protein (APP) is a transmembrane protein mostly recognized for its association with Alzheimer's disease. The physiological function of APP is still not completely understood much because of the redundancy between genes in the APP family. In this study we have used zebrafish to study the physiological function of the zebrafish APP homologue, appb, during development. We show that appb is expressed in post-mitotic neurons in the spinal cord. Knockdown of appb by 50-60% results in a behavioral phenotype with increased spontaneous coiling and prolonged touch-induced activity. The spinal cord motor neurons in these embryos show defective formation and axonal outgrowth patterning. Reduction in Appb also results in patterning defects and changed density of pre- and post-synapses in the neuromuscular junctions. Together, our data show that development of functional locomotion in zebrafish depends on a critical role of Appb in the patterning of motor neurons and neuromuscular junctions.
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| 2. |
- Harnek, Jan, et al.
(författare)
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Intimal Hyperplasia in Balloon Dilated Coronary Arteries is Reduced by Local Delivery of the NO Donor, SIN-1 Via a cGMP-Dependent Pathway.
- 2011
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Ingår i: BMC Cardiovascular Disorders. - : Springer Science and Business Media LLC. - 1471-2261. ; 11:1
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: To elucidate the mechanism by which local delivery of 3-morpholino-sydnonimine (SIN-1) affects intimal hyperplasia after percutaneous transluminal coronary angioplasty (PTCA). METHODS: Porcine coronary arteries were treated with PTCA and immediately afterwards locally treated for 5 minutes, with a selective cytosolic guanylate cyclase inhibitor, 1 H-(1,2,4)oxadiazole(4,3-alpha)quinoxaline-1-one (ODQ) + SIN-1 or only SIN-1 using a drug delivery-balloon. Arteries were angiographically depicted, morphologically evaluated and analyzed after one and eight weeks for actin, myosin and intermediate filaments (IF) and nitric oxide synthase (NOS) contents. RESULTS: Luminal diameter after PCI in arteries treated with SIN-1 alone and corrected for age-growth was significantly larger as compared to ODQ + SIN-1 or to controls (p < 0.01). IF/actin ratio after one week in SIN-1 treated segments was not different compared to untreated segments, but was significantly reduced compared to ODQ + SIN-1 treated vessels (p < 0.05). Expression of endothelial NADPH diaphorase activity was significantly lower in untreated segments and in SIN-1 treated segments compared to controls and SIN-1 + ODQ treated arteries (p < 0.01). Restenosis index (p < 0.01) and intimal hyperplasia (p < 0.01) were significantly reduced while the residual lumen was increased (p < 0.01) in SIN-1 segments compared to controls and ODQ + SIN-1 treated vessels. CONCLUSIONS: After PTCA local delivery of high concentrations of the NO donor SIN-1 for 5 minutes inhibited injury induced neointimal hyperplasia. This favorable effect was abolished by inhibition of guanylyl cyclase indicating mediation of a cyclic guanosine 3',5'-monophosphate (cGMP)-dependent pathway. The momentary events at the time of injury play crucial role in the ensuring development of intimal hyperplasia.
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| 3. |
- Lindqvist, Johan, 1985-
(författare)
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Cellular and Molecular Mechanisms Underlying Congenital Myopathy-related Weakness
- 2014
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Congenital myopathies are a rare and heterogeneous group of diseases. They are primarily characterised by skeletal muscle weakness and disease-specific pathological features. They harshly limit ordinary life and in severe cases, these myopathies are associated with early death of the affected individuals. The congenital myopathies investigated in this thesis are nemaline myopathy and myofibrillar myopathy. These diseases are usually caused by missense mutations in genes encoding myofibrillar proteins, but the exact mechanisms by which the point mutations in these proteins cause the overall weakness remain mysterious. Hence, in this thesis two different nemaline myopathy-causing actin mutations and one myofibrillar myopathy-causing myosin-mutation found in both human patients and mouse models were used to investigate the cascades of molecular and cellular events leading to weakness.I performed a broad range of functional and structural experiments including skinned muscle fibre mechanics, small-angle X-ray scattering as well as immunoblotting and histochemical techniques. Interestingly, according to my results, point mutations in myosin and actin differently modify myosin binding to actin, cross-bridge formation and muscle fibre force production revealing divergent mechanisms, that is, gain versus loss of function (papers I, II and IV). In addition, one point mutation in actin appears to have muscle-specific effects. The presence of that mutant protein in respiratory muscles, i.e. diaphragm, has indeed more damaging consequences on myofibrillar structure than in limb muscles complexifying the pathophysiological mechanisms (paper II).As numerous atrophic muscle fibres can be seen in congenital myopathies, I also considered this phenomenon as a contributing factor to weakness and characterised the underlying causes in presence of one actin mutation. My results highlighted a direct muscle-specific up-regulation of the ubiquitin-proteasome system (paper III).All together, my research work demonstrates that mutation- and muscle-specific mechanisms trigger the muscle weakness in congenital myopathies. This gives important insights into the pathophysiology of congenital myopathies and will undoubtedly help in designing future therapies.
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| 4. |
- Murtada, Sae-Il, et al.
(författare)
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Experiments and mechanochemical modeling of smooth muscle contraction : Significance of filament overlap.
- 2012
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Ingår i: Journal of Theoretical Biology. - : Elsevier BV. - 0022-5193 .- 1095-8541. ; 297, s. 176-186
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Tidskriftsartikel (refereegranskat)abstract
- The main function of smooth muscle is to maintain/regulate the size of different hollow organs through contraction and relaxation. The magnitude of the active force during contraction is dependent on the number of attached cross-bridges, which can be linked to the overlap between the thin and thick filaments. The relevance of filament overlap and the active cross-bridges in smooth muscle is investigated through a mechanical model founded on Hill's three-element model. The mechanical model describes a sarcomere-equivalent contractile unit supported by structural observations with a distinct filament overlap and a realistic framework for the filament sliding behavior based on force-velocity experiments. The mechanical model is coupled to the four-state latch-model by Hai and Murphy to capture the electromechanical activation from intracellular calcium concentration to load-bearing cross-bridges. The model is fitted to isometric experiments performed on the pig carotid media and on isotonic quick-release experiments found in the literature. The proposed coupled mechanochemical model with the description of the filament overlap, which has a significant influence on the results, is able to predict isometric experimental data performed at different muscle lengths. The relevance of the filament overlap and the load-bearing cross-bridges is investigated through the model by simulating additional scenarios that has been documented in the literature.
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| 5. |
- Witman, Nevin, 1982-, et al.
(författare)
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Recapitulation of developmental cardiogenesis governs the morphological and functional regeneration of adult newt hearts following injury
- 2011
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Ingår i: Developmental Biology. - : Elsevier BV. - 0012-1606 .- 1095-564X. ; 354:1, s. 67-76
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Tidskriftsartikel (refereegranskat)abstract
- Urodele amphibians, like the newt, are the champions of regeneration as they are able to regenerate many body parts and tissues. Previous experiments, however, have suggested that the newt heart has only a limited regeneration capacity, similar to the human heart. Using a novel, reproducible ventricular resection model, we show for the first time that adult newt hearts can fully regenerate without any evidence of scarring. This process is governed by increased proliferation and the up-regulation of cardiac transcription factors normally expressed during developmental cardiogenesis. Furthermore, we are able to identify cells within the newly regenerated regions of the myocardium that express the LIM-homeodomain protein Istet1 and GATA4, transcription factors found in cardiac progenitors. Information acquired from using the newt as a model organism may help to shed light on the regeneration deficits demonstrated in damaged human hearts.
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