Validation and Application of an intervertebral Disc Finite Element Model Utilizing independently Constructed Tissue-Level Constitutive formulations That are Nonlinear, Anisotropic, and Time-Dependent

Finite element models are advantageous in the study of intervertebral disc mechanics as the stress-strain distributions can be determined throughout the tissue and the applied loading and material properties can be controlled and modified. However, the complicated nature of the disc presents a challenge in developing an accurate and predictive disc model, which has led to limitations in finite element geometries, material constitutive models and properties, and model validation. The objective of this dissertation is to develop a new finite element model of the intervertebral disc, to validate the model\u27s nonlinear and time-dependent responses without tuning or calibration, and to evaluate the effect of changes in nucleus pulposus and cartilaginous endplate material properties on the disc mechanical response. This was accomplished through a cohesive series of studies. First, structural hyperelastic constitutive models were used in conjunction with biphasic-swelling theory to obtain material parameters for the disc tissues from recent tissue tests. A new disc finite element model was then constructed utilizing an analytically-based geometry created from the mean shape of human L4/L5 discs, measured from high-resolution 3D MR images and averaged using signed distance functions. The full disc model was then validated against experimental intervertebral disc loading datasets for compressive slow loading ramp, creep, and stress-relaxation simulations, and finally the new disc model was used to investigate the role of each individual disc tissue. The significance of this new disc model is threefold. First, an extensive validation was performed using the full nonlinear response of the intervertebral disc in three different loading modalities. The finite element predictions fit within the experimental range (mean ±95% confidence interval) of the nonlinear response. Second, the validation was predictive; no material parameters were determined using fits to any motion-segment data. All parameters were obtained from fits to the individual tissue responses. Furthermore, the loading mechanisms tested at the tissue level (confined compression, uniaxial tension) were different than those implemented at the full disc scale (quasi-static slow ramp, creep, stress-relaxation). Lastly, model validation was accomplished without any tuning or adjustment of the material parameters in order to force agreement between the FE and experimental responses

A numerical investigation of hydrocarbon related magnetic signatures

The iron sulphide greigite (Fe3S4) is linked to important diagenetic processes in sediments and to hydrocarbon formation and migration. The magnetic properties of this ferrimagnetic mineral are relatively obscure because it is difficult to synthesise and because it is unstable and therefore thought to be irrelevant to the geological record. However, it is increasingly recognised that greigite can remain stable on geological timescales. It is important to understand the magnetic properties of greigite to identify its presence and timing of formation as it is a proxy for environmental magnetic studies and for hydrocarbon microseepage identification. In this thesis, numerical methods are used to study the magnetic properties of greigite. Using a micromagnetic finite-element method (FEM), important questions regarding the magnetic structure and palaeomagnetic recording fidelity of gregite are addressed. For equidimensional particles, the single-domain (SD) to single-vortex (SV) threshold is found to be $d_0\approx 54$ nm and only SV particles >70 nm to carry stable magnetisations over billion-year timescales. A simplified model is developed to study the hysteresis and first-order reversal curve (FORC) properties of non-interacting idealised SD greigite particles. To understand the effects of SV magnetisations on FORC properties, a micromagnetic FEM is used to simulate randomly oriented dispersions of non-interacting greigite in the SV size range. SV effects dominate the FORC signal for particles >70 nm. Implications for FORC diagram interpretation are discussed. Magnetic inter-particle interactions are known to effect the FORC response of magnetic particle ensembles. A micromagnetic FEM is used to study the FORC signal of randomly dispersed strongly interacting clusters of greigite. The FORC response of strongly interacting greigite is found to be similar to that of multi-domain (MD) particles. Since naturally occurring greigite is rarely in a MD state, it is concluded that in greigite-bearing rocks that produce MD-like FORC signals the origin of this signal should be attributed to strong interactions between the particles.Open Acces

Improvements to the APBS biomolecular solvation software suite

The Adaptive Poisson-Boltzmann Solver (APBS) software was developed to solve the equations of continuum electrostatics for large biomolecular assemblages that has provided impact in the study of a broad range of chemical, biological, and biomedical applications. APBS addresses three key technology challenges for understanding solvation and electrostatics in biomedical applications: accurate and efficient models for biomolecular solvation and electrostatics, robust and scalable software for applying those theories to biomolecular systems, and mechanisms for sharing and analyzing biomolecular electrostatics data in the scientific community. To address new research applications and advancing computational capabilities, we have continually updated APBS and its suite of accompanying software since its release in 2001. In this manuscript, we discuss the models and capabilities that have recently been implemented within the APBS software package including: a Poisson-Boltzmann analytical and a semi-analytical solver, an optimized boundary element solver, a geometry-based geometric flow solvation model, a graph theory based algorithm for determining p$K_a$ values, and an improved web-based visualization tool for viewing electrostatics

Differential evolution of non-coding DNA across eukaryotes and its close relationship with complex multicellularity on Earth

Here, I elaborate on the hypothesis that complex multicellularity (CM, sensu Knoll) is a major evolutionary transition (sensu Szathmary), which has convergently evolved a few times in Eukarya only: within red and brown algae, plants, animals, and fungi. Paradoxically, CM seems to correlate with the expansion of non-coding DNA (ncDNA) in the genome rather than with genome size or the total number of genes. Thus, I investigated the correlation between genome and organismal complexities across 461 eukaryotes under a phylogenetically controlled framework. To that end, I introduce the first formal definitions and criteria to distinguish ‘unicellularity’, ‘simple’ (SM) and ‘complex’ multicellularity. Rather than using the limited available estimations of unique cell types, the 461 species were classified according to our criteria by reviewing their life cycle and body plan development from literature. Then, I investigated the evolutionary association between genome size and 35 genome-wide features (introns and exons from protein-coding genes, repeats and intergenic regions) describing the coding and ncDNA complexities of the 461 genomes. To that end, I developed ‘GenomeContent’, a program that systematically retrieves massive multidimensional datasets from gene annotations and calculates over 100 genome-wide statistics. R-scripts coupled to parallel computing were created to calculate >260,000 phylogenetic controlled pairwise correlations. As previously reported, both repetitive and non-repetitive DNA are found to be scaling strongly and positively with genome size across most eukaryotic lineages. Contrasting previous studies, I demonstrate that changes in the length and repeat composition of introns are only weakly or moderately associated with changes in genome size at the global phylogenetic scale, while changes in intron abundance (within and across genes) are either not or only very weakly associated with changes in genome size. Our evolutionary correlations are robust to: different phylogenetic regression methods, uncertainties in the tree of eukaryotes, variations in genome size estimates, and randomly reduced datasets. Then, I investigated the correlation between the 35 genome-wide features and the cellular complexity of the 461 eukaryotes with phylogenetic Principal Component Analyses. Our results endorse a genetic distinction between SM and CM in Archaeplastida and Metazoa, but not so clearly in Fungi. Remarkably, complex multicellular organisms and their closest ancestral relatives are characterized by high intron-richness, regardless of genome size. Finally, I argue why and how a vast expansion of non-coding RNA (ncRNA) regulators rather than of novel protein regulators can promote the emergence of CM in Eukarya. As a proof of concept, I co-developed a novel ‘ceRNA-motif pipeline’ for the prediction of “competing endogenous” ncRNAs (ceRNAs) that regulate microRNAs in plants. We identified three candidate ceRNAs motifs: MIM166, MIM171 and MIM159/319, which were found to be conserved across land plants and be potentially involved in diverse developmental processes and stress responses. Collectively, the findings of this dissertation support our hypothesis that CM on Earth is a major evolutionary transition promoted by the expansion of two major ncDNA classes, introns and regulatory ncRNAs, which might have boosted the irreversible commitment of cell types in certain lineages by canalizing the timing and kinetics of the eukaryotic transcriptome.:Cover page Abstract Acknowledgements Index 1. The structure of this thesis 1.1. Structure of this PhD dissertation 1.2. Publications of this PhD dissertation 1.3. Computational infrastructure and resources 1.4. Disclosure of financial support and information use 1.5. Acknowledgements 1.6. Author contributions and use of impersonal and personal pronouns 2. Biological background 2.1. The complexity of the eukaryotic genome 2.2. The problem of counting and defining “genes” in eukaryotes 2.3. The “function” concept for genes and “dark matter” 2.4. Increases of organismal complexity on Earth through multicellularity 2.5. Multicellularity is a “fitness transition” in individuality 2.6. The complexity of cell differentiation in multicellularity 3. Technical background 3.1. The Phylogenetic Comparative Method (PCM) 3.2. RNA secondary structure prediction 3.3. Some standards for genome and gene annotation 4. What is in a eukaryotic genome? GenomeContent provides a good answer 4.1. Background 4.2. Motivation: an interoperable tool for data retrieval of gene annotations 4.3. Methods 4.4. Results 4.5. Discussion 5. The evolutionary correlation between genome size and ncDNA 5.1. Background 5.2. Motivation: estimating the relationship between genome size and ncDNA 5.3. Methods 5.4. Results 5.5. Discussion 6. The relationship between non-coding DNA and Complex Multicellularity 6.1. Background 6.2. Motivation: How to define and measure complex multicellularity across eukaryotes? 6.3. Methods 6.4. Results 6.5. Discussion 7. The ceRNA motif pipeline: regulation of microRNAs by target mimics 7.1. Background 7.2. A revisited protocol for the computational analysis of Target Mimics 7.3. Motivation: a novel pipeline for ceRNA motif discovery 7.4. Methods 7.5. Results 7.6. Discussion 8. Conclusions and outlook 8.1. Contributions and lessons for the bioinformatics of large-scale comparative analyses 8.2. Intron features are evolutionarily decoupled among themselves and from genome size throughout Eukarya 8.3. “Complex multicellularity” is a major evolutionary transition 8.4. Role of RNA throughout the evolution of life and complex multicellularity on Earth 9. Supplementary Data Bibliography Curriculum Scientiae Selbständigkeitserklärung (declaration of authorship

Research in cosmic and gamma ray astrophysics

Discussed here is research in cosmic ray and gamma ray astrophysics at the Space Radiation Laboratory (SRL) of the California Institute of Technology. The primary activities discussed involve the development of new instrumentation and techniques for future space flight. In many cases these instrumentation developments were tested in balloon flight instruments designed to conduct new investigations in cosmic ray and gamma ray astrophysics. The results of these investigations are briefly summarized. Specific topics include a quantitative investigation of the solar modulation of cosmic ray protons and helium nuclei, a study of cosmic ray positron and electron spectra in interplanetary and interstellar space, the solar modulation of cosmic rays, an investigation of techniques for the measurement and interpretation of cosmic ray isotopic abundances, and a balloon measurement of the isotopic composition of galactic cosmic ray boron, carbon, and nitrogen

A technique for solving certain Wiener-Hopf type boundary value problems Technical report no. 9

Technique for solving Weiner-Hopf type boundary value problem