The role of sarcoplasmic calcium in skeletal muscle training adaptation

Current research shows a clear correlation between strong mitochondrial capacity, healthy muscle and general public health. A sedentary lifestyle increases the risk of a whole host of so called ‘western diseases’, while an active lifestyle reduce the risk of said diseases. Thus, well-functioning muscles are a necessity for general health. So far endurance exercise is the most effective method to improve muscle function. This thesis will focus on the cellular mechanisms that regulate muscle performance and how these can be improved. In the first study, we show that supplemented dietary nitrate enhances Ca2+ handling and submaximal force in mouse fast twitch muscle. Continuing this, in study two, we show that the increased submaximal force enhances voluntary activity in mice, presumably due to a shifted perceived effort of running. In study three we show that mild stress from cold exposure can enhance mitochondrial biogenesis resulting in improved fatigue resistance without exercise. The cold environment seems to induce a sarcoplasmic reticulum (SR) Ca2+ leak in the skeletal muscle. In study four we investigated why short (180s) high intensity interval training works better for enhancing endurance than regular low-intensity exercise. We show that oxidants formed during exercise causes ryanodine receptor modifications, which result in a SR Ca2+ leak and this in turn likely triggers transcription to improved mitochondrial capacity. In study five we show that inducing a mild SR Ca2+ leak, either with exercise or pharmacological tools, drive mitochondrial biogenesis. In study six we show that a in a model of ageing, a degenerative mitochondrial problem causes myopathy via reduced SR Ca2+ release. Ca2+ is a central player in muscle function. This thesis shows that diet, exercise and age have the ability to affect skeletal muscle Ca2+ handling. Most importantly, Ca2+ signals can improve mitochondrial function, resulting in improved muscle function. However degenerative mitochondria causes reduced Ca2+handling that leads to muscle weakness. This is one of the reasons an active lifestyle is so important for the elderly, because it improves the mitochondrial function rather than being degraded. Perhaps in the future, inducing a small SR Ca2+ leak could minimize some of the risks associated with sedentary lifestyle

NK cells are activated and primed for skin-homing during acute dengue virus infection in humans

10.1038/s41467-019-11878-3Nature Communications101389

Topology optimization of non-linear, dissipative structures and materials

Topology optimization is a mathematical tool for finding optimal distributions of material phases within a design domain. It is commonly used in early design stages to generate conceptual structural layouts. Ultimately, designs generated by topology optimization consist of distinct material phases with enhanced performance. Most research on topology optimization methods focuses on linear elastic mechanical problems with the objective to maximize stiffness. Whereas linear problems are well understood, methods for solving geometrically and/or material non-linear, transient, path-dependent problems are less so. This thesis consists of a general introductory part and six appended papers in which topology optimization frameworks that account for non-linear response are presented. The introductory part gives an overview of topology optimization methods, motivates optimization for non-linear problems and details the specific solution methods for the non-linear, transient and path-dependent frameworks on which the included papers are based on.All papers but Paper E present non-linear optimization frameworks that employ hyperelastic material models and are based on finite strain theory. In Papers A and B, topology optimization methods for multiple material phases and for tangent stiffness maximization, respectively, are established. It is shown that an arbitrary number of phases can be included in the optimization and that the optimized distribution of the phases depends on the load magnitude. It is also shown that the definition of the stiffness measure used in topology optimization of non-linear elastic structures is of great importance. In Papers C, D and F, inelastic constitutive models are included in the optimization frameworks. Rate-dependent, i.e. viscous, inertial and finite strain effects are combined with topology optimization to generate maximum energy absorbing structures. Both macroscopic structures and microstructural designs are presented, wherein plastic work is optimized. It is shown that micro and macro response can be tailored for a specific load magnitude, loading rate and load path. The developed scheme in Paper F enables optimization of structures for maximum stiffness while constraining the maximum specific plastic work. Since significant plasticity occurs at design domain boundaries, a regularization technique for explicit control of boundary effects in topology optimization problems, presented in Paper E, is utilized. This optimization approach shows that by constraining the specific plastic work, stiff designs with smooth stress distributions are generated

Elektroniskt Skyttesystem : Ett Elektroniskt & Matematiskt tillvägagångssätt

This dissertation describes a project to create an electronic shooting system made of simple and inexpensive components, namely a Raspberry Pi computer and sound detectors. The initial goals are to create a system that can be used with an acceptable precision. Secondly a performance analysis will be carried out to determine the precision that can be obtained using these components. The project was developed into three modules: back-end, Cloud and front-end. The back-end is used to gather the information of a projectile on the target, calculate the coordinates and send it to the Cloud. The Cloud acts as the interface between the back-end with the front-end. Lastly the front-end is the Viewer Client that presents the score and positon at which the projectile hit the target. After developing all the components and applications there was a functional system, but not a reliable system. This combination of Raspberry Pi and sound detectors were not good enough to obtain the precision required for the system to work as an electronic scoring system

Topology optimization of finite strain viscoplastic systems under transient loads

A transient finite strain viscoplastic model is implemented in a gradient-based topology optimization framework to design impact mitigating structures. The model's kinematics relies on the multiplicative split of the deformation gradient, and the constitutive response is based on isotropic hardening viscoplasticity. To solve the mechanical balance laws, the implicit Newmark-beta method is used together with a total Lagrangian finite element formulation. The optimization problem is regularized using a partial differential equation filter and solved using the method of moving asymptotes. Sensitivities required to solve the optimization problem are derived using the adjoint method. To demonstrate the capability of the algorithm, several protective systems are designed, in which the absorbed viscoplastic energy is maximized. The numerical examples demonstrate that transient finite strain viscoplastic effects can successfully be combined with topology optimization

Topology optimization for designing periodic microstructures based on finite strain viscoplasticity

This paper presents a topology optimization framework for designing periodic viscoplastic microstructures under finite deformation. To demonstrate the framework, microstructures with tailored macroscopic mechanical properties, e.g., maximum viscoplastic energy absorption and prescribed zero contraction, are designed. The simulated macroscopic properties are obtained via homogenization wherein the unit cell constitutive model is based on finite strain isotropic hardening viscoplasticity. To solve the coupled equilibrium and constitutive equations, a nested Newton method is used together with an adaptive time-stepping scheme. A well-posed topology optimization problem is formulated by restriction using filtration which is implemented via a periodic version of the Helmholtz partial differential equation filter. The optimization problem is iteratively solved with the method of moving asymptotes, where the path-dependent sensitivities are derived using the adjoint method. The applicability of the framework is demonstrated by optimizing several two-dimensional continuum composites exposed to a wide range of macroscopic strains

Ca²⁺, heat, and mitochondrial biogenesis.

<p>The contraction of skeletal muscle fibers is initiated by sarcoplasmic reticulum (SR) Ca²⁺ release via the ryanodine receptors (RyR), which is triggered by action potential activation of the transverse tubular voltage sensors, the dihydropyridine receptors (DHPR). Ca²⁺ activates the contractile machinery and is subsequently pumped back into the SR via SERCA (dashed arrows). α-Actinin 3 deficiency results in increased protein expression of SERCA and the SR Ca²⁺ buffers calsequestrin (CSQ) (grey arrows) and sarcalumenin (not shown). These changes are accompanied by increased SR Ca²⁺ leak and, subsequently, increased Ca²⁺ reuptake (red arrows), which generates heat. Increased [Ca²⁺] in the cytosol can trigger calcineurin (CaN) and calmodulin kinase (CaMK), resulting in PGC-1α activation (blue arrows) and subsequent mitochondrial biogenesis (green arrow).</p

Consistent boundary conditions for PDE filter regularization in topology optimization

Design variables in density-based topology optimization are typically regularized using filtering techniques. In many cases, such as stress optimization, where details at the boundaries are crucially important, the filtering in the vicinity of the design domain boundary needs special attention. One well-known technique, often referred to as “padding,” is to extend the design domain with extra layers of elements to mitigate artificial boundary effects. We discuss an alternative to the padding procedure in the context of PDE filtering. To motivate this augmented PDE filter, we make use of the potential form of the PDE filter which allows us to add penalty terms with a clear physical interpretation. The major advantages of the proposed augmentation compared with the conventional padding is the simplicity of the implementation and the possibility to tune the boundary properties using a scalar parameter. Analytical results in 1D and numerical results in 2D and 3D confirm the suitability of this approach for large-scale topology optimization

Plastic work constrained elastoplastic topology optimization

An elastoplastic topology optimization framework for limiting plastic work generation while maximizing stiffness is presented. The kinematics and constitutive model are based on finite strain linear isotropic hardening plasticity, and the balance laws are solved using a total Lagrangian finite element formulation. Aggregation of the specific plastic work combined with an adaptive normalization scheme efficiently constrains the maximum specific plastic work. The optimization problem is regularized using an augmented partial differential equation filter, and is solved by the method of moving asymptotes where path-dependent sensitivities are derived using the adjoint method. The numerical examples show a clear dependence on the optimized maximum stiffness structures for different levels of constrained specific plastic work. It is also shown that due to the history dependency of the plasticity, the load path significantly influences the structural performance and optimized topology