| 1. |
- Berthomier, M., et al.
(författare)
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Alfven : magnetosphere-ionosphere connection explorers
- 2012
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Ingår i: Experimental astronomy. - Dordrecht : Springer. - 0922-6435 .- 1572-9508. ; 33:2-3, s. 445-489
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Tidskriftsartikel (refereegranskat)abstract
- The aurorae are dynamic, luminous displays that grace the night skies of Earth's high latitude regions. The solar wind emanating from the Sun is their ultimate energy source, but the chain of plasma physical processes leading to auroral displays is complex. The special conditions at the interface between the solar wind-driven magnetosphere and the ionospheric environment at the top of Earth's atmosphere play a central role. In this Auroral Acceleration Region (AAR) persistent electric fields directed along the magnetic field accelerate magnetospheric electrons to the high energies needed to excite luminosity when they hit the atmosphere. The "ideal magnetohydrodynamics" description of space plasmas which is useful in much of the magnetosphere cannot be used to understand the AAR. The AAR has been studied by a small number of single spacecraft missions which revealed an environment rich in wave-particle interactions, plasma turbulence, and nonlinear acceleration processes, acting on a variety of spatio-temporal scales. The pioneering 4-spacecraft Cluster magnetospheric research mission is now fortuitously visiting the AAR, but its particle instruments are too slow to allow resolve many of the key plasma physics phenomena. The Alfv,n concept is designed specifically to take the next step in studying the aurora, by making the crucial high-time resolution, multi-scale measurements in the AAR, needed to address the key science questions of auroral plasma physics. The new knowledge that the mission will produce will find application in studies of the Sun, the processes that accelerate the solar wind and that produce aurora on other planets.
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| 2. |
- Randerath, W J, et al.
(författare)
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Non-CPAP therapies in obstructive sleep apnoea
- 2011
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Ingår i: European Respiratory Journal. - : European Respiratory Society. - 0903-1936 .- 1399-3003. ; 37:5, s. 1000-1028
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Tidskriftsartikel (refereegranskat)abstract
- In view of the high prevalence and the relevant impairment of patients with obstructive sleep apnoea syndrome (OSAS) lots of methods are offered which promise definitive cures for or relevant improvement of OSAS. This report summarises the efficacy of alternative treatment options in OSAS. An interdisciplinary European Respiratory Society task force evaluated the scientific literature according to the standards of evidence-based medicine. Evidence supports the use of mandibular advancement devices in mild to moderate OSAS. Maxillomandibular osteotomy seems to be as efficient as continuous positive airway pressure (CPAP) in patients who refuse conservative treatment. Distraction osteogenesis is usefully applied in congenital micrognathia or midface hypoplasia. There is a trend towards improvment after weight reduction. Positional therapy is clearly inferior to CPAP and long-term compliance is poor. Drugs, nasal dilators and apnoea triggered muscle stimulation cannot be recommended as effective treatments of OSAS at the moment. Nasal surgery, radiofrequency tonsil reduction, tongue base surgery, uvulopalatal flap, laser midline glossectomy, tongue suspension and genioglossus advancement cannot be recommended as single interventions. Uvulopalatopharyngoplasty, pillar implants and hyoid suspension should only be considered in selected patients and potential benefits should be weighed against the risk of long-term side-effects. Multilevel surgery is only a salvage procedure for OSA patients.
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| 3. |
- Forsyth, C., et al.
(författare)
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Temporal evolution and electric potential structure of the auroral acceleration region from multispacecraft measurements
- 2012
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Ingår i: Journal of Geophysical Research. - 0148-0227 .- 2156-2202. ; 117:12, s. A12203-
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Tidskriftsartikel (refereegranskat)abstract
- Bright aurorae can be excited by the acceleration of electrons into the atmosphere in violation of ideal magnetohydrodynamics. Modeling studies predict that the accelerating electric potential consists of electric double layers at the boundaries of an acceleration region but observations suggest that particle acceleration occurs throughout this region. Using multispacecraft observations from Cluster, we have examined two upward current regions on 14 December 2009. Our observations show that the potential difference below C4 and C3 changed by up to 1.7 kV between their respective crossings, which were separated by 150 s. The field-aligned current density observed by C3 was also larger than that observed by C4. The potential drop above C3 and C4 was approximately the same in both crossings. Using a novel technique of quantitively comparing the electron spectra measured by Cluster 1 and 3, which were separated in altitude, we determine when these spacecraft made effectively magnetically conjugate observations, and we use these conjugate observations to determine the instantaneous distribution of the potential drop in the AAR. Our observations show that an average of 15% of the potential drop in the AAR was located between C1 at 6235 km and C3 at 4685 km altitude, with a maximum potential drop between the spacecraft of 500 V, and that the majority of the potential drop was below C3. Assuming a spatial invariance along the length of the upward current region, we discuss these observations in terms of temporal changes and the vertical structure of the electrostatic potential drop and in the context of existing models and previous single- and multispacecraft observations.
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| 4. |
- Jansson, S. -A, et al.
(författare)
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Socioeconomic evaluation of well-characterized allergy to staple foods in adults
- 2014
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Ingår i: Allergy. European Journal of Allergy and Clinical Immunology. - : Wiley. - 0105-4538 .- 1398-9995. ; 69:9, s. 1241-1247
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Tidskriftsartikel (refereegranskat)abstract
- Background: The aim of the present study was to evaluate if total, direct, indirect, and intangible costs differ between a cohort of adults with well-characterized allergy to staple foods ('cases') and controls. Methods: Swedish adults with objectively diagnosed food allergy to cow's milk, hen's egg, and/or wheat were recruited at an outpatient allergy clinic. Controls age- and sex-matched to cases were recruited from the same geographic area. For assessing the household costs of food allergy, a disease-specific socioeconomic questionnaire, developed within EuroPrevall, was utilized. Results: Overall annual total costs at the household level were significantly higher among adults with food allergy compared with controls (the difference amounted to 8164 (sic) ), whereas direct costs did not differ between cases and controls. However, household healthcare costs and costs for medicines were significantly higher for cases vs controls. Furthermore, indirect costs were significantly higher for households with food-allergic adults vs households without food-allergic adults. Specifically, more time was spent on performing domestic tasks due to a family member's food-allergy-related illness, as well as shopping and preparing food, and seeking food-allergy-related information. Presence of food allergy also affected intangible costs. Adults with food allergy experienced overall lower health status compared with controls. Conclusions: Swedish adults with allergy to staple foods have higher total costs determined as direct, indirect, and intangible costs using the disease-specific socioeconomic questionnaire. Thus, total costs were 8164 (sic) higher per year in households with at least one adult allergic to staple foods compared with controls.
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| 5. |
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| 6. |
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| 7. |
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| 8. |
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| 9. |
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| 10. |
- Breed, Martin, 1981-, et al.
(författare)
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Pollen diversity matters : revealing the neglected effect of pollen diversity on fitness in fragmented landscapes
- 2012
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Ingår i: Molecular Ecology. - : Wiley. - 0962-1083 .- 1365-294X. ; 21:24, s. 5955-5968
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Tidskriftsartikel (refereegranskat)abstract
- Few studies have documented the impacts of habitat fragmentation on plant mating patterns together with fitness. Yet, these processes require urgent attention to better understand the impact of contemporary landscape change on biodiversity and for guiding native plant genetic resource management. We examined these relationships using the predominantly insect-pollinated Eucalyptus socialis. Progeny were collected from trees located in three increasingly disturbed landscapes in southern Australia and were planted out in common garden experiments. We show that individual mating patterns were increasingly impacted by lower conspecific density caused by habitat fragmentation. We determined that reduced pollen diversity probably has effects over and above those of inbreeding on progeny fitness. This provides an alternative mechanistic explanation for the indirect density dependence often inferred between conspecific density and offspring fitness.
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| 11. |
- Hewitt, Dominic, et al.
(författare)
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A hydrodynamic comparison of solution and gas phase proteins and their complexes.
- 2014
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Ingår i: Journal of Physical Chemistry B. - : American Chemical Society (ACS). - 1520-6106 .- 1520-5207. ; 118:29
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Tidskriftsartikel (refereegranskat)abstract
- The extent to which protein structures are preserved on transfer from solution to gas phase is a central question for native mass spectrometry. Here we compare the collision cross sections (Ω) of a wide range of different proteins and protein complexes (15-500 kDa) with their corresponding Stokes radii (RS). Using these methods, we find that Ω and RS are well correlated, implying overall preservation of protein structure in the gas phase. Accounting for protein hydration, a scaling term is required to bring Ω and RS into parity. Interestingly, the magnitude of this scaling term agrees almost entirely with the drag factor proposed by Millikan. RS were then compared with various different predicted values of Ω taken from their atomic coordinates. We find that many of the approaches used to obtained Ω from atomic coordinates miscalculate the physical sizes of the proteins in solution by as much as 20%. Rescaling of Ω estimated from atomic coordinates may therefore seem appropriate as a general method to bring theoretical values in line with those observed in solution.
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| 12. |
- Marklund, U, et al.
(författare)
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Domain-specific control of neurogenesis achieved through patterned regulation of Notch ligand expression
- 2010
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Ingår i: Development (Cambridge, England). - : The Company of Biologists. - 1477-9129 .- 0950-1991. ; 137:3, s. 437-445
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Tidskriftsartikel (refereegranskat)abstract
- Homeodomain (HD) transcription factors and components of the Notch pathway [Delta1 (Dll1), Jagged1 (Jag1) and the Fringe (Fng) proteins] are expressed in distinct progenitor domains along the dorsoventral (DV) axis of the developing spinal cord. However, the internal relationship between these two regulatory pathways has not been established. In this report we show that HD proteins act upstream of Notch signalling. Thus, HD proteins control the spatial distribution of Notch ligands and Fng proteins, whereas perturbation of the Notch pathway does not affect the regional expression of HD proteins. Loss of Dll1 or Jag1 leads to a domain-specific increase of neuronal differentiation but does not affect the establishment of progenitor domain boundaries. Moreover, gain-of-function experiments indicate that the ability of Dll1 and Jag1 to activate Notch is limited to progenitors endogenously expressing the respective ligand. Fng proteins enhance Dll1-activated Notch signalling and block Notch activation mediated by Jag1. This finding, combined with the overlapping expression of Fng with Dll1 but not with Jag1, is likely to explain the domain-specific activity of the Notch ligands. This outcome is opposite to the local regulation of Notch activity in most other systems, including the Drosophila wing, where Fng co-localizes with Jagged/Serrate rather than Dll/Delta, which facilitates Notch signalling at regional boundaries instead of within domains. The regulation of Notch activation in the spinal cord therefore appears to endow specific progenitor populations with a domain-wide autonomy in the control of neurogenesis and prevents any inadequate activation of Notch across progenitor domain boundaries.
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| 13. |
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| 14. |
- Bachinger, Angelika, et al.
(författare)
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Stiffness-modifiable composite for pedestrian protection
- 2014
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Ingår i: 16th European Conference on Composite Materials, ECCM 2014. - : European Conference on Composite Materials, ECCM. - 9780000000002
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Konferensbidrag (refereegranskat)abstract
- A novel functional material allowing stiffness-reduction upon external stimulation was developed. Implementation of such technology in the design of a car front has high potential to result in increased protection of vulnerable road users (VRUs). The composite material is obtained by coating carbon fibres with a thermoplastic polymer in a continuous process, followed by infusion with an epoxy resin. The process is scalable for industrial use. The coating process was optimized regarding coating efficiency, energy consumption, risks involved for operating personnel and environment, and tailored to gain the optimal coating thickness obtained from numerical calculations. A drastic decrease in transversal stiffness could be detected for the composite material by dynamic mechanical thermal analysis (DMTA), when the temperature was increased above the glass transition temperature of the thermoplastic interphase. The ability of the material to achieve such temperature and associated reduction in stiffness by the application of current was verified using a special 3-point bending setup developed for this task.
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| 15. |
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| 18. |
- Hansson, EM, et al.
(författare)
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Control of Notch-ligand endocytosis by ligand-receptor interaction
- 2010
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Ingår i: Journal of cell science. - : The Company of Biologists. - 1477-9137 .- 0021-9533. ; 123:17Pt 17, s. 2931-2942
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Tidskriftsartikel (refereegranskat)abstract
- In Notch signaling, cell-bound ligands activate Notch receptors on juxtaposed cells, but the relationship between ligand endocytosis, ubiquitylation and ligand-receptor interaction remains poorly understood. To study the specific role of ligand-receptor interaction, we identified a missense mutant of the Notch ligand Jagged1 (Nodder, Ndr) that failed to interact with Notch receptors, but retained a cellular distribution that was similar to wild-type Jagged1 (Jagged1WT) in the absence of active Notch signaling. Both Jagged1WT and Jagged1Ndr interacted with the E3 ubiquitin ligase Mind bomb, but only Jagged1WT showed enhanced ubiquitylation after co-culture with cells expressing Notch receptor. Cells expressing Jagged1WT, but not Jagged1Ndr, trans-endocytosed the Notch extracellular domain (NECD) into the ligand-expressing cell, and NECD colocalized with Jagged1WT in early endosomes, multivesicular bodies and lysosomes, suggesting that NECD is routed through the endocytic degradation pathway. When coexpressed in the same cell, Jagged1Ndr did not exert a dominant-negative effect over Jagged1WT in terms of receptor activation. Finally, in Jag1Ndr/Ndr mice, the ligand was largely accumulated at the cell surface, indicating that engagement of the Notch receptor is important for ligand internalization in vivo. In conclusion, the interaction-dead Jagged1Ndr ligand provides new insights into the specific role of receptor-ligand interaction in the intracellular trafficking of Notch ligands.
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| 19. |
- Jansson, Sven-Arne, et al.
(författare)
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Health-related quality of life, assessed with a disease-specific questionnaire, in Swedish adults suffering from well-diagnosed food allergy to staple foods
- 2013
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Ingår i: Clinical and Translational Allergy. - : Wiley. - 2045-7022. ; 3:21
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Tidskriftsartikel (refereegranskat)abstract
- BackgroundOur aim was to investigate the factors that affect health related quality of life (HRQL) in adult Swedish food allergic patients objectively diagnosed with allergy to at least one of the staple foods cow’s milk, hen’s egg or wheat. The number of foods involved, the type and severity of symptoms, as well as concomitant allergic disorders were assessed.MethodsThe disease-specific food allergy quality of life questionnaire (FAQLQ-AF), developed within EuroPrevall, was utilized. The questionnaire had four domains: Allergen Avoidance and Dietary Restrictions (AADR), Emotional Impact (EI), Risk of Accidental Exposure (RAE) and Food Allergy related Health (FAH). Comparisons were made with the outcome of the generic questionnaire EuroQol Health Questionnaire, 5 Dimensions (EQ-5D). The patients were recruited at an outpatient allergy clinic, based on a convincing history of food allergy supplemented by analysis of specific IgE to the foods in question. Seventy-nine patients participated (28 males, 51 females, mean-age 41 years).ResultsThe domain with the most negative impact on HRQL was AADR, assessing the patients’ experience of dietary restrictions. The domain with the least negative impact on HRQL was FAH, relating to health concerns due to the food allergy. One third of the patients had four concomitant allergic disorders, which had a negative impact on HRQL. Furthermore, asthma in combination with food allergy had a strong impact. Anaphylaxis, and particularly prescription of an epinephrine auto-injector, was associated with low HRQL. These effects were not seen using EQ-5D. Analyses of the symptoms revealed that oral allergy syndrome and cardiovascular symptoms had the greatest impact on HRQL. In contrast, no significant effect on HRQL was seen by the number of food allergies.ConclusionsThe FAQLQ-AF is a valid instrument, and more accurate among patients with allergy to staple foods in comparison to the commonly used generic EQ-5D. It adds important information on HRQL in food allergic adults. We found that the restrictions imposed on the patients due to the diet had the largest negative impact on HRQL. Both severity of the food allergy and the presence of concomitant allergic disorders had a profound impact on HRQL.
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| 20. |
- Lange, Dale J., et al.
(författare)
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Pyrimethamine decreases levels of SOD1 in leukocytes and cerebrospinal fluid of ALS patients : A phase I pilot study
- 2013
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Ingår i: Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration. - London : Informa Healthcare. - 2167-8421 .- 2167-9223. ; 14:3, s. 199-204
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Tidskriftsartikel (refereegranskat)abstract
- The mutated SOD1 protein appears to have a gene dose-dependent effect on the severity and progression of ALS. Lowering of SOD1 protein levels might reduce severity and progression of the disease. The antimalarial drug pyrimethamine (PYR) was identified to cause a dose-dependent reduction in SOD1 protein levels in human cells in vitro. To determine if there was a similar effect in humans, we performed a phase I pilot study in 16 ALS patients with SOD1 mutations, 18 weeks in duration. Blood samples were obtained during all visits. The actin normalized leukocyte SOD1 levels were analyzed using Western blot. SOD1 content in the cerebrospinal fluid (CSF) was determined by ELISA and the SOD1 enzymic activity by spectrophotometric analysis using KO2. Clinical assessment of disease severity was assessed using Appel ALS scale and ALSFRS-R. The leukocyte SOD1 levels showed a significant reduction (p < 0.0001) by the third study visit and this reduction was sustained throughout the remainder of the study. CSF also showed a decrease in SOD1 protein content and enzymic activity in the two patients so tested. Thus, PYR use may be associated with a reduction in SOD1 in ALS patients. The significance is uncertain and further detailed study is required.
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| 21. |
- Lek, M, et al.
(författare)
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A homeodomain feedback circuit underlies step-function interpretation of a Shh morphogen gradient during ventral neural patterning
- 2010
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Ingår i: Development (Cambridge, England). - : The Company of Biologists. - 1477-9129 .- 0950-1991. ; 137:23, s. 4051-4060
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Tidskriftsartikel (refereegranskat)abstract
- The deployment of morphogen gradients is a core strategy to establish cell diversity in developing tissues, but little is known about how small differences in the concentration of extracellular signals are translated into robust patterning output in responding cells. We have examined the activity of homeodomain proteins, which are presumed to operate downstream of graded Shh signaling in neural patterning, and describe a feedback circuit between the Shh pathway and homeodomain transcription factors that establishes non-graded regulation of Shh signaling activity. Nkx2 proteins intrinsically strengthen Shh responses in a feed-forward amplification and are required for ventral floor plate and p3 progenitor fates. Conversely, Pax6 has an opposing function to antagonize Shh signaling, which provides intrinsic resistance to Shh responses and is important to constrain the inductive capacity of the Shh gradient over time. Our data further suggest that patterning of floor plate cells and p3 progenitors is gated by a temporal switch in neuronal potential, rather than by different Shh concentrations. These data establish that dynamic, non-graded changes in responding cells are essential for Shh morphogen interpretation, and provide a rationale to explain mechanistically the phenomenon of cellular memory of morphogen exposure.
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| 22. |
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| 23. |
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| 24. |
- Marklund, Göran T., et al.
(författare)
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Cluster multipoint study of the acceleration potential pattern and electrodynamics of an auroral surge and its associated horn arc
- 2012
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Ingår i: Journal of Geophysical Research. - 0148-0227 .- 2156-2202. ; 117:10, s. A10223-
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Tidskriftsartikel (refereegranskat)abstract
- Cluster results are presented from the acceleration region of an auroral surge and connected horn arc, observed during an extended time period of substorm activity. The Cluster spacecraft crossed different magnetic local time (MLT) sectors of the surge and horn, with lag times of 2-10 min. Acceleration potential patterns are derived for the horn arc and for the double arc (surge and horn) at the surge front and deeper into the surge. The parallel potential drop of the horn arc ranged between 4 and 7 kV. At the surge front, two weakly coupled U-potentials with parallel potential drops of 8 (7) kV and 7 (5) kV were derived for the surge and horn, respectively, from the C3 (C4) data. A similar, more coupled pattern was derived for the region deeper into the surge. We also address how the field-aligned currents of the surge and horn system close in the ionosphere. The Cluster data allow almost simultaneous estimates of the latitudinal current closure at various MLT sectors. Significant net upward currents are derived for the horn and surge, whereas the currents at the surge front were found to be balanced. The net upward horn current is proposed to be fed by the zonal divergence of the westward Pedersen current in the horn, consistent with the acceleration potential decrease in the westward horn direction. The net upward surge current is proposed to be fed by the divergence of a westward electrojet and by localized downward currents adjacent to the surge.
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| 25. |
- Marklund, Göran T., et al.
(författare)
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Evolution in space and time of the quasi-static acceleration potential of inverted-V aurora and its interaction with Alfvenic boundary processes
- 2011
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Ingår i: Journal of Geophysical Research. - 0148-0227 .- 2156-2202. ; 116, s. A00K13-
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Tidskriftsartikel (refereegranskat)abstract
- Results are presented from Cluster crossings of the acceleration region of two inverted-V auroras located in the poleward part of an extensive substorm bulge. The particle and field data are used to infer the acceleration potentials of the arcs and their distribution in altitude and latitude. The C1 data are consistent with a symmetric potential pattern, composed of two negative U potentials and one positive U potential in between, and the C3 and C4 data are consistent with an asymmetric pattern, where the dominating potential structure extends deep into the polar cap boundary (PCB) region. The two patterns may either correspond to different stages of evolution of the same double arc system or represent two longitudinally separated double arc systems. For all spacecraft, the potential well of the poleward arc extends into the PCB region, whereas the density cavity does not but remains confined to R1. This suggests that the Alfvenic activity observed within the PCB region prevents the cavity formation, consistent with the associated FACs being roughly balanced over this region. The results show that Alfvenic and quasi-static acceleration operates jointly in the PCB region, varying from being about equally important (on C1) to being predominantly quasi-static (on C3/C4). The presence (absence) of an upward electron beam, associated with a positive potential structure and a downward current, observed by C1 (C4/C3) is expected from its short life time, shorter than the time lag between the Cluster spacecraft. The evolution involves both a broadening and a density reduction of the associated downward current sheet to below the critical current density above which parallel electric fields will form. The deepest potential well of 13 kV observed by C4 was located in Region 1, adjacent to the PCB region and coinciding with the deepest density cavity, with a minimum density of 0.1 cm(-3). The interface between Region 1 and the PCB region, coinciding with the steep density gradient, appears to be the leading edge of the cavity.
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| 26. |
- Marklund, Matti, et al.
(författare)
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A Dietary Biomarker Approach Captures Compliance and Cardiometabolic Effects of a Healthy Nordic Diet in Individuals with Metabolic Syndrome.
- 2014
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Ingår i: Journal of Nutrition. - : Elsevier BV. - 1541-6100 .- 0022-3166. ; 144:10, s. 1642-1649
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Tidskriftsartikel (refereegranskat)abstract
- Assessment of compliance with dietary interventions is necessary to understand the observed magnitude of the health effects of the diet per se. To avoid reporting bias, different dietary biomarkers (DBs) could be used instead of self-reported data. However, few studies investigated a combination of DBs to assess compliance and its influence on cardiometabolic risk factors. The objectives of this study were to use a combination of DBs to assess compliance and to investigate how a healthy Nordic diet (ND) influences cardiometabolic risk factors in participants with high apparent compliance compared with the whole study population. From a recently conducted isocaloric randomized trial, SYSDIET (Systems Biology in Controlled Dietary Interventions and Cohort Studies), in 166 individuals with metabolic syndrome, several DBs were assessed to reflect different key components of the ND: canola oil (serum phospholipid α-linolenic acid), fatty fish [eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA)], vegetables (plasma β-carotene), and whole grains (plasma alkylresorcinols). High-fat dairy intake (expectedly low in the ND) was reflected by serum pentadecanoic acid. All participants with biomarker data (n = 154) were included in the analyses. Biomarkers were combined by using a biomarker rank score (DB score) and principal component analysis (PCA). The DB score was then used to assess compliance. During the intervention, median concentrations of alkylresorcinols, α-linolenic acid, EPA, and DHA were >25% higher in the ND individuals compared with the controls (P < 0.05), whereas median concentrations of pentadecanoic acid were 14% higher in controls (P < 0.05). Median DB score was 57% higher in the ND compared with controls (P < 0.001) during the intervention, and participants were ranked similarly by DB score and PCA score. Overall, estimates of group difference in cardiometabolic effects generally appeared to be greater among compliant participants than in the whole study population (e.g., estimates of treatment effects on blood pressure and lipoproteins were ∼1.5- to 2-fold greater in the most compliant participants), suggesting that poor compliance attenuated the dietary effects. With adequate consideration of their limitations, DB combinations (e.g., DB score) could be useful for assessing compliance in intervention studies investigating cardiometabolic effects of healthy dietary patterns. The study was registered at clinicaltrials.gov as NCT00992641.
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| 27. |
- Marklund, Mattias, et al.
(författare)
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Gauge-free Hamiltonian structure of the spin Maxwell-Vlasov equations
- 2011
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Ingår i: Physics Letters A. - : Elsevier BV. - 0375-9601 .- 1873-2429. ; 375:24, s. 2362-2365
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Tidskriftsartikel (refereegranskat)abstract
- We derive the gauge-free Hamiltonian structure of an extended kinetic theory, for which the intrinsic spin of the particles is taken into account. Such a semi-classical theory can be of interest for describing, e.g., strongly magnetized plasma systems. We find that it is possible to construct a generalized noncanonical Poisson bracket on the extended phase space, and discuss the implications of our findings, including stability of monotonic equilibria. (C) 2011 Elsevier B.V. All rights reserved.
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| 32. |
- Zetterström, Per, 1980-
(författare)
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Misfolded superoxide dismutase-1 in amyotrophic lateral sclerosis
- 2011
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Amyotrophic lateral sclerosis (ALS) is a disease in which the motor neurons die in a progressive manner, leading to paralysis and muscle wasting. ALS is always fatal, usually through respiratory failure when the disease reaches muscles needed for breathing. Most cases are sporadic, but approximately 5–10% are familial. The first gene to be linked to familial ALS encodes the antioxidant enzyme superoxide dismutase-1 (SOD1). Today, more than 160 different mutations in SOD1 have been found in ALS patients. The mutant SOD1 proteins cause ALS by gain of a toxic property that should be common to all. Aggregates of SOD1 in motor neurons are hallmarks of ALS patients and transgenic models carrying mutant SOD1s, suggesting that misfolding, oligomerization, and aggregation of the protein may be involved in the pathogenesis. SOD1 is normally a very stable enzyme, but the structure has several components that make SOD1 sensitive to misfolding. The aim of the work in this thesis was to study misfolded SOD1 in vivo.Small amounts of soluble misfolded SOD1 were identified as a common denominator in transgenic ALS models expressing widely different forms of mutant SOD1, as well as wild-type SOD1. The highest levels of misfolded SOD1 were found in the vulnerable spinal cord. The amounts of misfolded SOD1 were similar in all the different models and showed a broad correlation with the lifespan of the different mouse strains. The misfolded SOD1 lacked the C57-C146 intrasubunit disulfide bond and the stabilizing zinc and copper ions, and was prinsipally monomeric. Forms with higher apparent molecular weights were also found, some of which might be oligomers. Misfolding-prone monomeric SOD1 appeared to be the principal source of misfolded SOD1 in the CNS. Misfolded SOD1 in the spinal cord was found to interact mainly with chaperones, with Hsc70 being the most important. Only a minor proportion of the Hsc70 was sequestered by SOD1, however, suggesting that chaperone depletion is not involved in ALS. SOD1 is normally found in the cytoplasm but can be secreted. Extracellular mutant SOD1 has been found to be toxic to motor neurons and glial cells. Misfolded SOD1 in the extracellular space could be involved in the spread of the disease between different areas of the CNS and activate glial cells known to be important in ALS. The best way to study the interstitium of the CNS is through the cerebrospinal fluid (CSF), 30% of which is derived from the interstitial fluid. Antibodies specific for misfolded SOD1 were used to probe CSF from ALS patients and controls for misfolded SOD1. We did find misfolded SOD1 in CSF, but at very low levels, and there was no difference between ALS patients and controls. This argues against there being a direct toxic effect of extracellular SOD1 in ALS pathogenesis.In conclusion, soluble misfolded SOD1 is a common denominator for transgenic ALS model mice expressing widely different mutant SOD1 proteins. The misfolded SOD1 is mainly monomeric, but also bound to chaperones, and possibly exists in oligomeric forms also. Misfolded SOD1 in the interstitium might promote spread of aggregation and activate glial cells, but it is too scarce to directly cause cytotoxicity.
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