Myosin subfragment-2 (S2) is an intrinsically unstable coiled coil. This dissertation tests if the mechanical stability of myosin S2 would influence the availability of myosin S1 heads to actin thin filaments. The elevated instability in myosin S2 coiled coil could be one of the causes for hypercontractility in Familial Hypertrophic Cardiomyopathy (FHC). As hypothesized FHC mutations, namely E924K and E930del, in myosin S2 displayed an unstable myosin S2 coiled coil compared to wild type as measured by Fluorescence Resonant Energy Transfer (FRET) and gravitational force spectroscopy (GFS). To remedy this, anti-S2 peptides; the stabilizer and the destabilizer peptides by namesake were designed in our lab to increase and decrease the stability of myosin S2 coiled coil to influence the actomyosin interaction. Firstly, the effectiveness of anti-S2 peptides were tested on muscle myosin S2 peptides across MYH11 (smooth), MYH7 (cardiac), and MYH2 (skeletal) with GFS and FRET. The results demonstrated that the mechanical stability was increased by the stabilizer and decreased by the destabilizer across the cardiac and skeletal myosin S2 isoform but not for the smooth muscle isoform. The destabilizer peptide had dissociation binding constants of 9.97 × 10-1 μM to MYH7 isoform, 1.00 μM to MYH2 isoform, and no impact on MYH11, and the stabilizer peptide had dissociation binding constants of 2.12 × 10-2 μM to MYH7 isoform, 3.41 × 10-1 μM to MYH2 isoform, and no impact on MYH11 revealed by FRET. In presence of the stabilizer, FRET assay, affinity of the E930del and E924K increased by 10.23 and 0.60 fold respectively. The force required to uncoil muscle myosin S2 peptides in the presence of the stabilizer peptide was more than in its absence in muscle myosin S2 isoforms of MYH7 (1.80 fold higher), MYH2 (1.40 fold higher), and E930del (2.60 fold higher) and no change for MYH11 compared to control. The force required to uncoil muscle myosin S2 in presence of the destabilizer was less than in its absence in both MYH7 (2.00 fold lower) and MYH2 (2.5 fold lower) but the same for MYH11 compared to their controls. Both FRET and GFS assays demonstrated that both anti-S2 peptides do not have any impact on smooth muscle myosin S2 isoform. In FRET assay, there was no significant difference in the lifetime value in the presence or absence of anti-S2 peptides in smooth muscle myosin S2. In GFS assay, there was no significant difference in the force required to uncoil the dimer in presence or absence of the anti-S2 peptides smooth muscle myosin S2. Effectively, the stabilizer peptide improved the stability of FHC mutant (E924K and E930del) myosin S2 peptide. FHC mutations showed high lifetime value in FRET assay and low force to uncoil coiled coil myosin S2 in GFS assay. In the presence of the stabilizer, lifetime value decreased in FRET assay and more force was required to uncoil myosin S2 coiled coil in GFS assay. This study demonstrated that structure of muscle myosin S2 can be altered by small peptides. The stabilizer peptide enhanced dimer formation in wild type and mutant cardiac, and skeletal myosin S2 peptides, and destabilizer increased flexibility of cardiac and skeletal myosin S2 wild type peptide. Neither anti-S2 peptides had impacts on smooth muscle myosin S2 isoform. The study thus effectively demonstrates the mechanical stability of myosin S2 coiled coil in striated muscle system could be modified using the specific anti-S2 peptides. Stabilizer of the anti-S2 peptide was effective to remedy the dampened stability of FHC myosin S2 coiled coil thus providing a new dimension of treating cardiovascular and skeletal muscle disorders by targeting the structural property of muscle proteins.

Myosin subfragment-2 (S2) is a coiled coil linker between myosin subfragment-1 and light meromyosin (LMM). This dissertation examines whether the myosin S2 coiled coil could regulate the amount of myosin S1 heads available to bind actin thin filaments by modulating the stability of its coiled coil. A stable myosin S2 coiled coil would have less active myosin S1 heads compared to a more flexible myosin S2 coiled coil, thus causing increased force production through acto-myosin interaction. The stability of the myosin S2 coiled coil was modulated by the binding of a natural myosin S2 binding protein, myosin binding protein C (MyBPC), and synthetic myosin S2 binding proteins, stabilizer and destabilizer peptide, to myosin S2. Competitive enzyme linked immunosorbent assay (cELISA) experiments revealed the cross specificity and high binding affinity of the synthetic peptides to the myosin S2 of human cardiac and rabbit skeletal origins. Gravitational force spectroscopy (GFS) was performed to test the stability of myosin S2 coiled coil in the presence of these myosin S2 binding proteins. GFS experiments demonstrated the stabilization of the myosin S2 coiled coil by the binding of MyBPC and stabilizer peptide to myosin S2, while the binding of destabilizer peptide to the same resulted in a flexible myosin S2 coiled coil. The binding of MyBPC and stabilizer peptide respectively, resulted in 3.35 and 1.5 times increase in force required to uncoil the myosin S2, while the binding of destabilizer peptide resulted in 1.6 times decrease in force required to uncoil the myosin S2. The myofibrillar contractility assay was performed to test the effect of synthetic myosin S2 binding proteins on the sarcomere shortening in myofibrils. The stabilizer peptide resulted in decreased sarcomere shortening of myofibrils as a result of decreased acto-myosin interaction, on the other hand, the binding of destabilizer peptide caused an increase in sarcomere shortening. The in vitro motility assay was performed to test the effect of altered stability of myosin S2 by binding of these myosin S2 binding proteins on the motility of actin filaments sliding over myosin. The motility of actin filaments was hindered by treating myosin thick filaments with whole length skeletal MyBPC or by treating heavy meromyosin with stabilizer peptide, while the motility of actin filaments was enhanced when heavy meromyosin was treated with destabilizer peptide. This study demonstrates that the myosin S2 coiled coil stability influences the force produced by acto-myosin interaction in striated skeletal muscle. The myosin S2 coiled coil when stabilized by MyBPC and stabilizer peptide resulted in decreased force production by reduced acto-myosin interaction. While the binding of destabilizer resulted in a flexible myosin S2 coiled coil and increased force production by enhanced acto-myosin interaction. The potentially cooperative response of contractility to the instability of the S2 coiled coil promises that this biological mechanism may be the target of drugs to modulate muscle performance.

Our brain, perhaps the most sophisticated and mysterious part of the human body, to some extent, determines who we are. However, it’s a vulnerable organ. When subjected to an impact, such as a traffic accident or sport, it may lead to traumatic brain injury (TBI) which can have devastating effects for those who suffer the injury. Despite lots of efforts have been put into primary injury prevention, the number of TBIs is still on an unacceptable high level in a global perspective. Brain edema is a major neurological complication of moderate and severe TBI, which consists of an abnormal accumulation of fluid within the brain parenchyma. Clinically, local and minor edema may be treated conservatively only by observation, where the treatment of choice usually follows evidence-based practice. In the first study, the gravitational force is suggested to have a significant impact on the pressure of the edema zone in the brain tissue. Thus, the objective of the study was to investigate the significance of head position on edema at the posterior part of the brain using a Finite Element (FE) model. The model revealed that water content (WC) increment at the edema zone remained nearly identical for both supine and prone positions. However, the interstitial fluid pressure (IFP) inside the edema zone decreased around 15% by having the head in a prone position compared with a supine position. The decrease of IFP inside the edema zone by changing patient position from supine to prone has the potential to alleviate the damage to axonal fibers of the central nervous system. These observations suggest that considering the patient’s head position during intensive care and at rehabilitation should be of importance to the treatment of edematous regions in TBI patients. In TBI patients with diffuse brain edema, for most severe cases with refractory intracranial hypertension, decompressive craniotomy (DC) is performed as an ultimate therapy. However, a complete consensus on its effectiveness has not been achieved due to the high levels of severe disability and persistent vegetative state found in the patients treated with DC. DC allows expansion of the swollen brain outside the skull, thereby having the potential in reducing the Intracranial Pressure (ICP). However, the treatment causes stretching of the axons and may contribute to the unfavorable outcome of the patients. The second study aimed at quantifying the stretching and WC in the brain tissue due to the neurosurgical intervention to provide more insight into the effects upon such a treatment. A nonlinear registration method was used to quantify the strain. Our analysis showed a substantial increase of the strain level in the brain tissue close to the treated side of DC compared to before the treatment. Also, the WC was related to specific gravity (SG), which in turn was related to the Hounsfield unit (HU) value in the Computerized Tomography (CT) images by a photoelectric correction according to the chemical composition of the brain tissue. The overall WC of brain tissue presented a significant increase after the treatment compared to the condition seen before the treatment. It is suggested that a quantitative model, which characterizes the stretching and WC of the brain tissue both before as well as after DC, may clarify some of the potential problems with such a treatment. Diffusion Weighted (DW) Imaging technology provides a noninvasive way to extract axonal fiber tracts in the brain. The aim of the third study, as an extension to the second study was to assess and quantify the axonal deformation (i.e. stretching and shearing)at both the pre- and post-craniotomy periods in order to provide more insight into the mechanical effects on the axonal fibers due to DC. Subarachnoid injection of artificial cerebrospinal fluid (CSF) into the CSF system is widely used in neurological practice to gain information on CSF dynamics. Mathematical models are important for a better understanding of the underlying mechanisms. Despite the critical importance of the parameters for accurate modeling, there is a substantial variation in the poroelastic constants used in the literature due to the difficulties in determining material properties of brain tissue. In the fourth study, we developed a Finite Element (FE) model including the whole brain-CSF-skull system to study the CSF dynamics during constant-rate infusion. We investigated the capacity of the current model to predict the steady state of the mean ICP. For transient analysis, rather than accurately fit the infusion curve to the experimental data, we placed more emphasis on studying the influences of each of the poroelastic parameters due to the aforementioned inconsistency in the poroelastic constants for brain tissue. It was found that the value of the specific storage term S_epsilon is the dominant factor that influences the infusion curve, and the drained Young’s modulus E was identified as the dominant parameter second to S_epsilon. Based on the simulated infusion curves from the FE model, Artificial Neural Network (ANN) was used to find an optimized parameter set that best fit the experimental curve. The infusion curves from both the FE simulations and using ANN confirmed the limitation of linear poroelasticity in modeling the transient constant-rate infusion. To summarize, the work done in this thesis is to introduce FE Modeling and imaging technologiesincluding CT, DW imaging, and image registration method as a complementarytechnique for clinical diagnosis and treatment of TBI patients. Hopefully, the result mayto some extent improve the understanding of these clinical problems and improve theirmedical treatments. / QC 20120201

The Vlasov-Poisson system is most commonly used to model the movement of charged particles in a plasma or of stars in a galaxy. It consists of a kinetic equation known as the Vlasov equation coupled with a force determined by the Poisson equation. The system in Euclidean space is well-known and has been extensively studied under various assumptions. In this paper, we derive the Vlasov-Poisson equations assuming the particles exist only on the 2-sphere, then take an in-depth look at particles which initially lie along a great circle of the sphere. We show that any great circle is an invariant set of the equations of motion and prove that the total energy, number of particles, and entropy of the system are conserved for circular initial distributions. / Graduate

Gas metal arc is a high-efficiency and widely used heat source for metal processing applied predominantly in welding and additive manufacturing. In this study, it was applied to welding. It offers high productivity, low production and investment cost, as well as suffers from some drawbacks such as humping or undercut when welding large parts that are curved and impose changing the orientation of the welding torch along the joint path. Deeper process understanding was therefore sought to mitigate these drawbacks. The difficulty is then the non-lineardependence of the process to the welding parameters and material properties. Besides, visual observation of this process is also difficult. For instance, the elevated temperature and the intense radiative emission from the electric arc, smoke, spatter, as well as the non-transparency of the processed alloy can hinder in-process observation or limit it. Process simulation provides a complementary means to reach process knowledge. It was thus the approach used in this study. For this, a thermo-fluid melt pool model that can predict melting and solidification, track free surface deformation, metal transfer, and coalescence with the melt pool was developed. Two main research questions were identified and addressed.The first one led to studying the effect of the substrate orientation during multilayer welding of a V-groove joint with INVAR and gas metal arc. It was foundthat the force balance in the melt pool changes significantly when the workpieceorientation is changed, resulting in distinct melt flow patterns, melt pool and bead geometries, and in some conditions defect initiation such as humping, undercut, and lack of fusion. As a result, multi-layer welding with flat substrate and downhill welding of a 20◦ inclined substrate are recommended with these process conditions. On the contrary, welding of a side inclined substrate and uphill welding of a 20◦ inclined substrate are not recommended. The second question gave rise to the comparative investigation of the three electromagnetic force models commonly used when modelling a melt pool produced by an electric arc. The underlying modelling assumptions were retrieved and investigated. It was found that each of these three models predicts a different melt flow pattern, different heat convection, melt pool shape, free surface oscillation, and interaction with the transferred metal drops, and thus result in different bead geometry. All these models can be adjusted to predict the penetration depth, however, only the most complete of them is recommended for developing a predictive melt pool model. For this, it is proposed as a future work to improve this model through predicting an electromagnetic force that takes also into account the local deformation of the free surface. / Gasmetallbåge är en effektiv och allmänt använd värmekälla vid svetsning och additiv tillverkning. I denna studie tillämpas den på svetsning. Den erbjuder hög produktivitet, låg kostnad vid inköp och användning, såväl som vissa nackdelarsom ojämn "bucklig" svetssträng och smältdiken vid svetsning av stora komponenter som är krökta och medför att svetsbrännarens orientering ändras utmed fogen. Bättre processförståelse eftersträvas därför för att mildra dessa nackdelar. En utmaning är processens icke-linjära beroende av svetsparametrarna och materialegenskaperna. Dessutom är experimentell optisk övervakning svår. Till exempel kan den höga temperaturen och den intensiva elektromagnetiska strålningen från ljusbågen, rök, sprut, såväl som legeringens ogenomskinlighet, förhindra observation under processen eller begränsa den. Processimulering erbjuder en komplementär metod för att nå processkunskap. Det är alltså detta tillvägagångssätt som används i denna studie. För detta har en modell av värme och materialflödena i smältan utvecklats som kan prediktera smältning och stelning, spåra smältytans deformation, metallflöde och koalescens med smältan.Två huvudsakliga forskningsfrågor har identifierats och adresserats. Den första studerade gravitationens påverkan vid flersträngs-, gasmetallbågsvetsning av V-fogar i INVAR. Olika svetslägen har visat sig ha en betydande påverkan på kraftbalanserna i svetssmältan vilket resulterar i distinkta smältflöden, smält- och svetsförbandgeometrier, och under vissa förhållanden svetsdefekter såsom ojämn "bucklig" svetssträng, smältdiken och bindfel. Som ett resultat rekommenderas horisontellt och 20◦ fallande läge vid flersträngssvetsning, medan 20◦ stigande och sidolutande inte rekommenderas. Den andra frågan undersökte inverkan av de tre huvudsakliga modellerna för den elektromagnetiska kraften som idag används vid svetssimuleringar. För modelleringen har antaganden lagts fram och undersökts. Det visade sig att de tre modellerna predikterar olika flödesmönster i smältan, olika värmekonvektion, smältgeometri, ytvågor och interaktion med de överförda metalldropparna, och därmed också predikterar olika svetsstränggeometrier. Alla tre modeller kan justeras för att prediktera svetspenetrationen, men endast den mest kompletta av dessa rekommenderas för sant prediktiv modellering. Det föreslås också att ytterligare förbättra den mest kompletta modellen så att det elektromagnetiska kraftfältet följer deformationen av den fria smältytan. / <p>Submitted papers or manuscripts have been excluded from the fulltext file. </p>

This thesis deals with stress, strain and reliability analysis of synchronous generator stator including an inhomogeneous temperature field. Using the finite element method, stress and strain are calculated, and from these values safety against yield strength is determined, which is followed by the life calculation of the most stressed weld joint and the determination of its possible damage during the period required by the customer.