On the Effectiveness of Rebuilding RNA Secondary Structures from Sequence Chunks

Despite the computing power of emerging technolo-gies, predicting long RNA secondary structures with thermodynamics-based methods is still infeasible, espe-cially if the structures include complex motifs such as pseu-doknots. This paper presents preliminary results on rebuilding RNA secondary structures by an extensive and systematic sampling of nucleotide chunks. The rebuilding approach merges the significant motifs found in the secondary struc-tures of the single chunks. The extensive sampling and pre-diction of nucleotide chunks are supported by grid tech-nology as part of the RNAVLab functionality. Significant motifs are identified in the chunk secondary structures and merged in a single structure based on their recurrences an

Prediction of secondary structures for large RNA molecules

The prediction of correct secondary structures of large RNAs is one of the unsolved challenges of computational molecular biology. Among the major obstacles is the fact that accurate calculations scale as O(n⁴), so the computational requirements become prohibitive as the length increases. We present a new parallel multicore and scalable program called GTfold, which is one to two orders of magnitude faster than the de facto standard programs mfold and RNAfold for folding large RNA viral sequences and achieves comparable accuracy of prediction. We analyze the algorithm's concurrency and describe the parallelism for a shared memory environment such as a symmetric multiprocessor or multicore chip. We are seeing a paradigm shift to multicore chips and parallelism must be explicitly addressed to continue gaining performance with each new generation of systems. We provide a rigorous proof of correctness of an optimized algorithm for internal loop calculations called internal loop speedup algorithm (ILSA), which reduces the time complexity of internal loop computations from O(n⁴) to O(n³) and show that the exact algorithms such as ILSA are executed with our method in affordable amount of time. The proof gives insight into solving these kinds of combinatorial problems. We have documented detailed pseudocode of the algorithm for predicting minimum free energy secondary structures which provides a base to implement future algorithmic improvements and improved thermodynamic model in GTfold. GTfold is written in C/C++ and freely available as open source from our website.M.S.Committee Chair: Bader, David; Committee Co-Chair: Heitsch, Christine; Committee Member: Harvey, Stephen; Committee Member: Vuduc, Richar

TARGETING AXON GROWTH FROM NEURONS TRANSPLANTEDINTO THE CENTRAL NERVOUS SYSTEM

Damage to the adult mammalian central nervous system (CNS), either by traumatic injury or disease, usually results in permanent sensory and/or motor deficits. Regeneration of neural circuits is limited both by the lack of growthpromoting molecules and by the presence of growth-inhibitory molecules in the mature brain and spinal cord. The research described here examines the therapeutic potential of viral vectors and neuronal transplants to reconstruct damaged neural pathways in the CNS. Experimental neural transplantation techniques often fall short of expectations because of limited transplant survival and insufficient neurite outgrowth to repair connections and induce behavioral recovery. These shortcomings are addressed in the current studies by virus-mediated expression of cell-specific neurotrophic and guidance molecules in the host brain prior to cell transplantation. The initial proof-of-principle studies show that viral vectors can be used to create axon-guidance pathways in the adult mammalian brain. With such pathways in place, subsequent transplantation of neurons leads to longdistance, targeted outgrowth of neurites. Application of this technique to a rat model of Parkinsons disease demonstrates that circuit reconstruction leads to functional recovery. For this study, rats were lesioned on one side of their brain with 6-hydroxydopamine to produce a hemiparkinsonian state. The motor deficit was confirmed by amphetamine-induced rotation testing and spontaneous motor asymmetry testing. The rats were then divided into experimental groups to receive lentivirus injections along a path between the substantia nigra (SN) and the striatum to express glial cell-line derived neurotrophic factor (GDNF), GDNF family receptor alpha-1 (GFR1), netrin-1 or green fluorescent protein (GFP, control). One group received combination injections of lenti-GDNF and lenti-GFR1. One week after virus injections, animals received transplants of embryonic midbrain dopaminergic neurons into their SNs. They were tested for motor asymmetry every two weeks for a total of eight weeks and then brain tissue was harvested for immunohistochemical analysis. Results demonstrate that virus-induced expression of GDNF and GFR1 supports growth of dopaminergic fibers from cells transplanted into the SN all the way to the striatum, and these animals have a significant reduction in both drug-induced and spontaneous motor asymmetry

Doctor of Philosophy

dissertationThis dissertation explores three key facets of software algorithms for custom hardware ray tracing: primitive intersection, shading, and acceleration structure construction. For the first, primitive intersection, we show how nearly all of the existing direct three-dimensional (3D) ray-triangle intersection tests are mathematically equivalent. Based on this, a genetic algorithm can automatically tune a ray-triangle intersection test for maximum speed on a particular architecture. We also analyze the components of the intersection test to determine how much floating point precision is required and design a numerically robust intersection algorithm. Next, for shading, we deconstruct Perlin noise into its basic parts and show how these can be modified to produce a gradient noise algorithm that improves the visual appearance. This improved algorithm serves as the basis for a hardware noise unit. Lastly, we show how an existing bounding volume hierarchy can be postprocessed using tree rotations to further reduce the expected cost to traverse a ray through it. This postprocessing also serves as the basis for an efficient update algorithm for animated geometry. Together, these contributions should improve the efficiency of both software- and hardware-based ray tracers

Examining bacterial variation with genome graphs and Nanopore sequencing

A bacterial species' genetic content can be remarkably fluid. The collection of genes found within a given species is called the pan-genome and is generally much larger than the gene repertoire of a single cell. A consequence of this pan-genome is that bacterial genomes are highly adaptable and thus variable. The dominant paradigm for analysing genetic variation relies on a central idea: all genomes in a species can be described as minor differences from a single reference genome, which serves as a coordinate system. As an introduction to this thesis, we outline why this approach is inadequate for bacteria and describe a new approach using genome graphs. In the first chapter, we present algorithms for de novo variant discovery within such genome graphs and evaluate their performance with empirical data. The remaining chapters address a question relating to a critical bacterial pathogen: can Nanopore sequencing of Mycobacterium tuberculosis provide high-quality public health information? We collect data from Madagascar, South Africa, and England to help answer this question. First, we assess outbreaks identified using single-reference and genome graph methods. Second, we evaluate antimicrobial resistance predictions and introduce a framework for using genome graphs to improve current methods. Lastly, we train an M. tuberculosis-specific Nanopore basecalling model with considerable accuracy improvement. Together, this thesis provides general methods for uncovering bacterial variation and applies them to an important global public health question.EMBL International PhD Programm

Evolution from the ground up with Amee – From basic concepts to explorative modeling

Evolutionary theory has been the foundation of biological research for about a century now, yet over the past few decades, new discoveries and theoretical advances have rapidly transformed our understanding of the evolutionary process. Foremost among them are evolutionary developmental biology, epigenetic inheritance, and various forms of evolu- tionarily relevant phenotypic plasticity, as well as cultural evolution, which ultimately led to the conceptualization of an extended evolutionary synthesis. Starting from abstract principles rooted in complexity theory, this thesis aims to provide a unified conceptual understanding of any kind of evolution, biological or otherwise. This is used in the second part to develop Amee, an agent-based model that unifies development, niche construction, and phenotypic plasticity with natural selection based on a simulated ecology. Amee is implemented in Utopia, which allows performant, integrated implementation and simulation of arbitrary agent-based models. A phenomenological overview over Amee’s capabilities is provided, ranging from the evolution of ecospecies down to the evolution of metabolic networks and up to beyond-species-level biological organization, all of which emerges autonomously from the basic dynamics. The interaction of development, plasticity, and niche construction has been investigated, and it has been shown that while expected natural phenomena can, in principle, arise, the accessible simulation time and system size are too small to produce natural evo-devo phenomena and –structures. Amee thus can be used to simulate the evolution of a wide variety of processes

Reticulate Evolution: Symbiogenesis, Lateral Gene Transfer, Hybridization and Infectious heredity

info:eu-repo/semantics/publishedVersio

Astrophysics in 2006

The fastest pulsar and the slowest nova; the oldest galaxies and the youngest stars; the weirdest life forms and the commonest dwarfs; the highest energy particles and the lowest energy photons. These were some of the extremes of Astrophysics 2006. We attempt also to bring you updates on things of which there is currently only one (habitable planets, the Sun, and the universe) and others of which there are always many, like meteors and molecules, black holes and binaries.Comment: 244 pages, no figure