Amyotrophic Lateral Sclerosis (ALS) is an always lethal motor neuron disease with unknown pathogenesis. Inhibitors of the molecular chaperone heat shock protein 90 (Hsp90) have limited neuroprotection in some models of motor neuron degeneration. However the direct effect of Hsp90 inhibition on motor neurons is unknown. Here we show that Hsp90 inhibition induced motor neuron death through activation of the P2X7 receptor. Motor neuron death required phosphatase and tensein homolog (PTEN)-mediated inhibition of the PI3K/AKT pathway leading to Fas receptor activation and caspase dependent death. The relevance of Hsp90 for motor neuron survival was investigated in mutant Cu/Zn superoxide dismutase (SOD) transgenic animal models for ALS. Nitrated Hsp90, a posttranslational modification known to induce cell death (Franco, Ye et al. 2013), was present in motor neurons after intracellular release of zinc deficient (Zn, D83S) and the SOD in which copper binding site was genetically ablated (Q) but not after copper deficient (Cu) wild type SOD. Zn deficient and Q mutant SOD induced motor neuron death in a peroxynitrite mediated and copper dependent mechanism. Nitrated Hsp90 was not detected in the spinal cord of transgenic animals for ALS-mutant SOD animal models until disease onset. Increased nitrated Hsp90 concentrations correlated with disease progression. Addition of Zn or Q SOD to nontransgenic brain homogenate treated with peroxynitrite led to an increase level of nitrotyrosine in comparison to wild type controls. However, in the same samples there was a 2 to 10 time increase in Hsp90 nitration as compared to nitrotyrosine. The selective increase is likely due to the binding of Hsp90 to Zn deficient and Q SOD as oppose to wild type SOD. These results suggest that Hsp90 nitration facilitated by mutant SOD may cause motor neuron degeneration in ALS. Targeted inhibition of nitrated Hsp90 may be a novel therapeutic approach for ALS. An alternative therapeutic strategy is to target the production of survival factors by glial cells. Riluzole is the only FDA approved drug for the treatment of ALS and it shows a small but significant increase in patient lifespan. Our results show that acute riluzole treatment stimulated trophic factor production by astrocytes and Schwann cells. However long-term exposure reversed and even inhibited the production of trophic factors, an observation that may explain the modest increase in patient survival in clinical trials. Discontinuous riluzole treatment can maintain elevated trophic factor levels and prevent trophic factor reduction in spinal cords of nontransgenic animals. These results suggest that discontinuous riluzole administration may improve ALS patient survival. In summary, we demonstrated that Hsp90 has an essential function in the regulation of motor neuron survival. We have also shown that Hsp90 was nitrated in the presence of mutant SOD and was present during symptom onset and increases as disease progresses, which may explain the toxic gain of function of mutant SOD. Finally we demonstrate a biphasic effect of riluzole on trophic factor production and propose changes in administration to improve effects in ALS patients.

As the solar wind reaches Mercury it interacts with the planet’s magnetic field slowing down, forming a bow shock in front of the planet and diverting the flow around it. Along with the solar wind comes the interplanetary magnetic field, an extension of the sun’s magnetic field. The interaction between the bow shock and the interplanetary magnetic field impacts the behaviour of the plasma both up- and downstream of the bow shock. An important factor is the angle between the normal to the bow shock surface and the interplanetary magnetic field, θBN. The angle can be divided into two categories: quasi-parallel for when θBN < 45° and quasi-perpendicular for θBN > 45°. It is expected for a quasi-parallel configuration to have stronger fluctuations in both the solar wind upstream of the bow shock and in the magnetosheath downstream caused by reflected particles backstreaming into the solar wind. Quasi-perpendicular configurations are expected to have less fluctuations in both regions due to fewer solar wind particles being reflected back. In this thesis this connection is investigated at the bow shock at Mercury using magnetic field data from the MESSENGER mission. By looking at the data when the spacecraft travels through the thin bow shock the local θBN angle can be calculated. The fluctuation level is then calculated as the standard deviation of the magnetic field in a 30 second period upstream and downstream of the crossing. The results found are unexpected as the correlation between θBN and the fluctuation levels are weaker and more uniformly distributed than expected compared to similar studies conducted at Earth using the Cluster satellites. This is most likely due to the smaller spatial scale of the Hermean system: the structures perpendicular to the interplanetary magnetic field of upstream activity, such as SLAMS, cover a greater proportion of the bow shock than at Earth allowing them to extend over into neighbouring regions of different θBN values, giving a more uniform distribution of the fluctuation levels. / När solvinden når Merkurius växelverkar den med planetens magnetfält och solvinden saktas ned och avledes till att flöda kring planeten. Då solvinden decelereras formas en chock framför planeten, bogchocken. Tillsammans med solvinden kommer det interplanetära magnetfältet, som är en förlängning av solens magnetfält. Växelverkan mellan bogchocken och det interplanetära magnetfältet påverkar plasmat både upp- och nedströms från bogchocken. En viktigt faktor är vinkeln mellan normalen till bogchocken och det interplanetära magnetfältet, θBN . Bogchocken kan delas in i två kategorier: kvasi-parallell då θBN < 45° och kvasi-vinkelrät då θBN > 45°. Vid kvasi-parallella förhållanden förväntas starkare fluktuationer i magnetfältet både uppströms i solvinden och nedströms i magnetskiktet, orsakat av reflekterade partiklar som färdas in i den inkommande solvinden. Kvasi-vinkelräta förhållanden förväntas ha mindre fluktuationer då färre partiklar reflekteras. I den här uppsatsen undersöks kopplingen vid Merkurius bogchock med data från rymdsonden MESSENGER. Genom att använda data då rymdsonden färdas igenom den tunna bogchocken kan det lokala värdet på θBN uträknas. Fluktuationsnivåerna räknas ut som standardavvikelsen av magnetfältet under en 30 sekundersperiod uppströms och nedströms från korsningen. Resultaten är ej som förväntade då kopplingen mellan θBN och fluktuationsnivån är mycket svagare och jämnt fördelade än förväntat, baserat på resultat från jorden från Cluster-satelliterna. Den mest troliga förklaringen är att Merkurius och dess bogchock är mindre än jordens: de strukturerna som är vinkelräta till det interplanetära magnetfältet hos uppströmsfenomen, t.ex SLAMS, täcker då en större proportion av bogchocken än vid jorden vilket tillåter dem att sträcka sig in i närliggande regioner med annorlunda θBN värden, vilket ger en mer jämn utbredning av fluktuationsnivåerna.

Since Venus is an unmagnetized planet, it doesn’t interact with the solar wind in the same way as planets with an intrinsic magnetic field do. Due to its conductive ionosphere, however, it still possesses an induced magnetosphere. Venus’s magnetosphere contains different boundaries, identified by changes in the plasma or magnetic field characteristics. The boundaries we studied in this project are the bow shock and the Ion Composition Boundary (ICB). Previous studies identified the boundaries’ locations and compared them with plasma measurements outside of the magnetosphere, finding how the boundaries react to varying solar wind upstream conditions. What has been more rarely done, instead, is to find the analytical dependency of the bow shock and ICB on the upstream conditions. This was the purpose of this project. Developing this comprehensive analytical model allows us to determine the location of the boundaries, once the upstream conditions are defined. We used a database of boundary crossings and upstream conditions measurements deriving from the Venus EXpress (VEX). The procedure we followed was first to divide the boundaries crossings into bins, analyzing one upstream condition at a time. Then, we fitted the crossings using analytical equations depending on geometrical parameters. For the bow shock we used a conic section with semi-latus rectum L and eccentricity ε as geometrical parameters, for the dayside ICB we used a circumference with the radius R as geometrical parameter. We fitted these geometrical parameters with the upstream conditions in each bin and found the final model. The final equation for the bow shock depends on the Interplanetary Magnetic Field (IMF) magnitude, the solar wind mass flux, and the angle between the IMF direction and the local shock normal. For the ICB the final equation depends on the solar wind energy flux and the solar Extreme UltraViolet (EUV) flux. Given these solar wind and IMF properties, the geometrical parameters of the boundaries are uniquely identified. Then, we were able to determine the boundaries’ locations and shapes with higher accuracy than the general fitting models that don’t consider upstream conditions. For the bow shock we improved the accuracy by 17%, for the ICB by 8%. / Eftersom Venus är en omagnetisk planet växelverkar den inte med solvinden på samma sätt som planeter med ett inneboende magnetfält. På grund av sin ledande jonosfär har den dock fortfarande en inducerad magnetosfär. Venus magnetosfär innehåller olika gränser, identifierade av förändringar i plasma- eller magnetfältets egenskaper. Gränserna vi studerade i det här projektet är bogshocken och Ion Composition Boundary (ICB). Tidigare studier identifierade gränsernas lägen och jämförde dem med plasmamätningar utanför magnetosfären, och hittade hur gränserna ändras med varierande solvind uppströms. Vad som har gjorts mer sällan är att hitta det analytiska beroendet av bogchocken och ICB på uppströmsförhållandena. Det var syftet med det här projektet. Genom att utveckla de här analytiska modellerna kan vi bestämma placering för gränserna när uppströmsförhållandena har definierats. Vi använde en databas med gränsövergångar och mätningar av uppströmsförhållanden härrörande från Venus EXpress (VEX). Proceduren vi följde var först att dela upp gränsövergångarna i dataintervall och analysera ett uppströmsläge i taget. Sedan anpassade korsningarna med hjälp av analytiska ekvationer beroende på geometriska parametrar. För bogshocken använde vi en konisk sektion med semi-latus rektum L och excentricitet ε som geometriska parametrar, för dagsida ICB använde vi en omkrets med radien R som geometrisk parameter. Vi anpassade de här geometriska parametrarna för olika uppströmsförhållanden och tog fram en modell. Den slutliga ekvationen för bogshocken beror på det interplanetära magnetfältets (IMF) magnitud, solvindens rörelsemängd och vinkeln mellan IMF och den lokala shocknormalen. För ICB beror den slutliga ekvationen på solvindenergiflödet och extrem ultraviolett (EUV) flöde. Med avseende på de här solvinds- och IMF-egenskaperna är de geometriska parametrarna för gränserna identifierade. Sedan kunde vi bestämma gränsernas placeringar och former med högre noggrannhet än de allmänna modellerna som inte tar hänsyn till uppströmsförhållanden. För bogchocken förbättrade vi noggrannheten med 17% och för ICB med 8%.

The solar wind is a supersonic flow of protons and electrons emitted in all directions from the sun. As the supersonic solar wind encounters Earth’s magnetic field, it creates the Earth’s bow shock, which increases the kinetic entropy of electrons passing through it. In this study, the aim is to analyze shock crossings of Earth’s bow shock in order to draw conclusions of which shock parameters that are important forkinetic entropy generation. Due to knowledge gained from an earlier study by M. Lindberg et al. [1], the shock crossings of interest in this study are quasi-perpendicular shocks with a low electron plasma beta. The data used is measured with the NASA MMS spacecraft and accessed through IRF Uppsala. As a result,a database with 13 shock crossings was created and the entropy change was related to, among other parameters, temperature and density change, shock angle, Alfv´en Mach number, ion ram pressure and upstream magnetic field. We found that a highAlfv´en Mach number related nearly proportionally to a large change in electron entropy for low electron plasma beta quasiperpendicularcollisionless shock crossing. / Solvinden består av protoner och elektroner som emitteras ut från solen i alla riktningar med enorma hastigheter. När dessa partiklar, med en hastighet som överstiger signalhastigheten, träffar Jordens magnetfält uppstår Jordens bågchock. Bågchocken ökar den kinetiska entropin hos elektroner som färdas genom den. För den här studien är målet att analysera chockkorsningar vid Jordens bågchock för att kunna dra slutsatser om vilka chockparametrar som är viktiga för generering av kinetisk entropi. Till följd av en tidigare studie av M. Lindberg et al. [1] är det endast kvasi-vinkelräta chockkorsningar med ett lågt plasma beta som denna studie avser. Den uppmätta datan erhålls från NASAs MMS satelliter och kan nås genom IRF Uppsala. Resultatet blev en databas med 13 chocker där entropiförändringen plottades mot bl. a. temperaturoch densitetsändring, chockvinkel, Alfve´n Machtal, jontrycket och magnetfältet uppströms. Det upptäcktes då att ett högt Alfve´n Mach-tal indikerade på en stor entropiökning hos kollisionslösa, kvasi-vinkelräta chockkorsningar med låga elektronplasmabeta. / Kandidatexjobb i elektroteknik 2022, KTH, Stockholm

Blast-induced mild traumatic brain injury (BImTBI) is one of the most common causes of traumatic brain injuries. BImTBI mechanisms are not well identified, as most previous blast-related studies were focused on the visible and fatal injuries. BImTBI is a hidden lesion and long-term escalation of related complications is considered a serious health care challenging due to lack of accurate data required for early diagnosis and intervention. The experimental studies presented in this thesis were performed to investigate aspects of blast shock wave mechanisms that might lead to mild traumatic brain injury. A compressed air-driven shock tube was designed and validated using finite element analysis (FEA) and experimental investigation. Two metal diaphragm types (steel and brass) with three thicknesses (0.127, 0.76, and 0.025mm) were utilized in the shock tube calibration experiment, as a new approach to generate shock wave. The consistency of generated shock waves was confirmed using a statistical assessment of the results by evaluating the shock waves parameters. The analysis results showed that the 0.127mm steel diaphragm induces a reliable shock waveform in the range of BImTB investigations. Evaluation of the shock wave impacts on the brain was examined using two sets of experiments. The first set was conducted using a gel brain model while the second set was performed using a physical head occupied with a gel brain model and supported by a neck model. The gel brain model in both the experimental studies was generated using silicone gel (Sylgard-527). The effects of tested models locations and orientations with respect to the shock tube exit were investigated by measuring the generated pressure wave within the brain model and acceleration. The results revealed that the pressure waveform and acceleration outcomes were greatly affected by the tested model orientations and locations in relation to the path of shock wave propagation. / Thesis / Doctor of Philosophy (PhD)

With the increased frequency of accidental and deliberate explosions, the response of civil infrastructure systems to blast loading has become a research topic of great interest. However, with the high cost and complex safety and logistical issues associated with live explosives testing, North American blast resistant construction standards (e.g. ASCE 59-11 & CSA S850-12) recommend the use of shock tubes to simulate blast loads and evaluate relevant structural response. This study aims first at developing a 2D axisymmetric shock tube model, implemented in ANSYS Fluent, a computational fluid dynamics (CFD) software, and then validating the model using the classical Sod’s shock tube problem solution, as well as available shock tube experimental test results. Subsequently, the developed model is compared to a more complex 3D model in terms of the pressure, velocity and gas density. The analysis results show that there is negligible difference between the two models for axisymmetric shock tube performance simulation. However, the 3D model is necessary to simulate non-axisymmetric shock tubes. The design of a shock tube depends on the intended application. As such, extensive analyses are performed in this study, using the developed 2D axisymmetric model, to evaluate the relationships between the blast wave characteristics and the shock tube design parameters. More specifically, the blast wave characteristics (e.g. peak reflected pressure, positive phase duration and the reflected impulse), were compared to the shock tube design parameters (e.g. the driver section pressure and length, the driven v section length, and perforation diameter and their locations). The results show that the peak reflected pressure increases as the driver pressure increases, while a decrease of the driven length increases the peak reflected pressure. In addition, the positive phase duration increases as both the driver length and driven length are increased. Finally, although shock tubes generally generate long positive phase durations, perforations located along the expansion section showed promising results in this study to generate short positive durations. Finally, the developed 2D axisymmetric model is used to optimize the dimensions of a proposed large-scale conical shock tube system developed for civil infrastructure blast response evaluation applications. The capabilities of this proposed shock tube system are further investigated by correlating its design parameters to a range of explosion threats identified by different hemispherical TNT charge weight and distance scenarios. / Thesis / Master of Applied Science (MASc)

Introduction: Sepsis impaired vascular integrity results in multiple organ failure. Circulating lactate level is positively correlated with sepsis-induced mortality. We investigated whether lactate plays a role in causing endothelial barrier dysfunction in sepsis. Methods: Polymicrobial sepsis was induced in mice by cecal ligation and puncture (CLP). Lactic acid was injected i.p. (pH 6.8, 0.5 g/kg body weight) 6 h after CLP or sham surgery. To elucidate the role of heat shock protein A12B (HSPA12B), wild-type, HSPA12B-transgenic, and endothelial HSPA12B-deficient mice were subjected to CLP or sham surgery. To suppress lactate signaling, 3OBA (120 μM) was injected i.p. 3 h before surgery. Vascular permeability was evaluated with the Evans blue dye penetration assay. Results: We found that administration of lactate elevated CLP-induced vascular permeability. Vascular endothelial cadherin (VE-cadherin), claudin 5, and zonula occluden 1 (ZO-1) play a crucial role in the maintenance of endothelial cell junction and vascular integrity. Lactate administration significantly decreased VE-cadherin, claudin 5, and ZO-1 expression in the heart of septic mice. Our in vitro data showed that lactate (10 mM) treatment disrupted VE-cadherin, claudin 5, and ZO-1 in endothelial cells. Mechanistically, we observed that lactate promoted VE-cadherin endocytosis by reducing the expression of HSPA12B. Overexpression of HSPA12B prevented lactate-induced VE-cadherin disorganization. G protein-coupled receptor 81 (GPR81) is a specific receptor for lactate. Inhibition of GPR81 with its antagonist 3OBA attenuated vascular permeability and reversed HSPA12B expression in septic mice. Conclusions: The present study demonstrated a novel role of lactate in promoting vascular permeability by decreasing VE-cadherin junctions and tight junctions in endothelial cells. The deleterious effects of lactate in vascular hyperpermeability are mediated via HSPA12B- and GPR81-dependent signaling.

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The modulation of galactic cosmic ray (GCR) Carbon in a north-south asymmetrical heliosphere is studied, using a two-dimensional numerical model that contains a solar wind termination shock (TS), a heliosheath, as well as particle drifts and diffusive shock re-acceleration of GCRs. The asymmetry in the geometry of the heliosphere is incorporated in the model by assuming a significant dependence on heliolatitude of the thickness of the heliosheath. As a result, the model allows comparisons of modulation in the north and south hemispheres during both magnetic polarity cycles of the Sun, and from solar minimum to moderate maximum conditions. When comparing the computed spectra between polar angles of 55o (approximating the Voyager 1 direction) and 125o (approximating the Voyager 2 direction), it is found that at kinetic energies E < 1:0 GeV/nuc the effects of the assumed asymmetry in the geometry of the heliosphere on the modulated spectra are insignificant up to 60 AU from the Sun, but become increasingly more significant with larger radial distances to reach a maximum inside the heliosheath. In contrast, with E > 1:0 GeV/nuc, these effects remained insignificant throughout the heliosphere even very close to the heliopause (HP). However, when the enhancement of both polar and radial perpendicular diffusion coefficients off the equatorial plane is assumed to differ from heliographic pole to pole, reflecting different modulation conditions between the two hemispheres, major differences in the computed intensities between the two Voyager directions are obtained throughout the heliosphere. The model is further improved by incorporating new information about the HP location and the relevant heliopause spectrum for GCR Carbon at E < 200 MeV/nuc based on the recent Voyager 1 observations. When comparing the computed solutions at the Earth with ACE observations taken during different solar modulation conditions, it is found that it is possible for the level of modulation at the Earth, when solar activity changes from moderate maximum conditions to solar minimum conditions, to exceed the total modulation between the HP and the Earth during solar minimum periods. In the outer heliosphere, reasonable compatibility with the corresponding Voyager observations is established when drifts are scaled down to zero in the heliosheath in both polarity cycles. The effects of neglecting drifts in the heliosheath are found to be more significant than neglecting the enhancement of polar perpendicular diffusion. Theoretical expressions for the scattering function required for the reduction of the drift coefficient in modulation studies are illustrated and implemented in the numerical model. It is found that when this scattering function decreases rapidly over the poles, the computed A < 0 spectra are higher than the A > 0 spectra at all energies at Earth primarily because of drifts, which is unexpected from a classical drift modeling point of view. Scenarios of this function with strong decreases over the polar regions seem realistic at and beyond the TS, where the solar wind must have a larger latitudinal dependence. / PhD (Space Physics), North-West University, Potchefstroom Campus, 2015

The modulation of galactic cosmic ray (GCR) Carbon in a north-south asymmetrical heliosphere is studied, using a two-dimensional numerical model that contains a solar wind termination shock (TS), a heliosheath, as well as particle drifts and diffusive shock re-acceleration of GCRs. The asymmetry in the geometry of the heliosphere is incorporated in the model by assuming a significant dependence on heliolatitude of the thickness of the heliosheath. As a result, the model allows comparisons of modulation in the north and south hemispheres during both magnetic polarity cycles of the Sun, and from solar minimum to moderate maximum conditions. When comparing the computed spectra between polar angles of 55o (approximating the Voyager 1 direction) and 125o (approximating the Voyager 2 direction), it is found that at kinetic energies E < 1:0 GeV/nuc the effects of the assumed asymmetry in the geometry of the heliosphere on the modulated spectra are insignificant up to 60 AU from the Sun, but become increasingly more significant with larger radial distances to reach a maximum inside the heliosheath. In contrast, with E > 1:0 GeV/nuc, these effects remained insignificant throughout the heliosphere even very close to the heliopause (HP). However, when the enhancement of both polar and radial perpendicular diffusion coefficients off the equatorial plane is assumed to differ from heliographic pole to pole, reflecting different modulation conditions between the two hemispheres, major differences in the computed intensities between the two Voyager directions are obtained throughout the heliosphere. The model is further improved by incorporating new information about the HP location and the relevant heliopause spectrum for GCR Carbon at E < 200 MeV/nuc based on the recent Voyager 1 observations. When comparing the computed solutions at the Earth with ACE observations taken during different solar modulation conditions, it is found that it is possible for the level of modulation at the Earth, when solar activity changes from moderate maximum conditions to solar minimum conditions, to exceed the total modulation between the HP and the Earth during solar minimum periods. In the outer heliosphere, reasonable compatibility with the corresponding Voyager observations is established when drifts are scaled down to zero in the heliosheath in both polarity cycles. The effects of neglecting drifts in the heliosheath are found to be more significant than neglecting the enhancement of polar perpendicular diffusion. Theoretical expressions for the scattering function required for the reduction of the drift coefficient in modulation studies are illustrated and implemented in the numerical model. It is found that when this scattering function decreases rapidly over the poles, the computed A < 0 spectra are higher than the A > 0 spectra at all energies at Earth primarily because of drifts, which is unexpected from a classical drift modeling point of view. Scenarios of this function with strong decreases over the polar regions seem realistic at and beyond the TS, where the solar wind must have a larger latitudinal dependence. / PhD (Space Physics), North-West University, Potchefstroom Campus, 2015