Machine Learning Guided Exploration of an Empirical Ribozyme Fitness Landscape

Okinawa Institute of Science and Technology Graduate UniversityDoctor of PhilosophyFitness landscape of a biomolecule is a representation of its activity as a function of its sequence. Properties of a fitness landscape determine how evolution proceeds. Therefore, the distribution of functional variants and more importantly, the connectivity of these variants within the sequence space are important scientific questions. Exploration of these spaces, however, is impeded by the combinatorial explosion of the sequence space. High-throughput experimental methods have recently reduced this impediment but only modestly. Better computational methods are needed to fully utilize the rich information from these experimental data to better understand the properties of the fitness landscape. In this work, I seek to improve this exploration process by combining data from massively parallel experimental assay with smart library design using advanced computational techniques. I focus on an artificial RNA enzyme or ribozyme that can catalyze a ligation reaction between two RNA fragments. This chemistry is analogous to that of the modern RNA polymeraseenzymes, therefore, represents an important reaction in the origin of life. In the first chapter, I discuss the background to this work in the context of evolutionary theory of fitness landscape and its implications in biotechnology. In chapter 2, I explore the use of processes borrowed from the field of evolutionary computation to solve optimization problems using real experimental sequence-activity data. In chapter 3, I investigate the use of supervised machine learning models to extract information on epistatic interactions from the dataset collected during multiple rounds of directed evolution. I investigate and experimentally validate the extent to which a deep learning model can be used to guide a completely computational evolutionary algorithm towards distant regions of the fitness landscape. In the final chapter, I perform a comprehensive experimental assay of the combinatorial region explored by the deep learning-guided evolutionary algorithm. Using this dataset, I analyze higher-order epistasis and attempt to explain the increased predictability of the region sampled by the algorithm. Finally, I provide the first experimental evidence of a large RNA ‘neutral network’. Altogether, this work represents the most comprehensive experimental and computational study of the RNA ligase ribozyme fitness landscape to date, providing important insights into the evolutionary search space possibly explored during the earliest stages of life.doctoral thesi

Simulated Annealing

The book contains 15 chapters presenting recent contributions of top researchers working with Simulated Annealing (SA). Although it represents a small sample of the research activity on SA, the book will certainly serve as a valuable tool for researchers interested in getting involved in this multidisciplinary field. In fact, one of the salient features is that the book is highly multidisciplinary in terms of application areas since it assembles experts from the fields of Biology, Telecommunications, Geology, Electronics and Medicine

Machine learning into metaheuristics: A survey and taxonomy of data-driven metaheuristics

During the last years, research in applying machine learning (ML) to design efficient, effective and robust metaheuristics became increasingly popular. Many of those data driven metaheuristics have generated high quality results and represent state-of-the-art optimization algorithms. Although various appproaches have been proposed, there is a lack of a comprehensive survey and taxonomy on this research topic. In this paper we will investigate different opportunities for using ML into metaheuristics. We define uniformly the various ways synergies which might be achieved. A detailed taxonomy is proposed according to the concerned search component: target optimization problem, low-level and high-level components of metaheuristics. Our goal is also to motivate researchers in optimization to include ideas from ML into metaheuristics. We identify some open research issues in this topic which needs further in-depth investigations

Integrative Modeling of Transcriptional Regulation in Response to Autoimmune Desease Therapies

Die rheumatoide Arthritis (RA) und die Multiple Sklerose (MS) werden allgemein als Autoimmunkrankheiten eingestuft. Zur Behandlung dieser Krankheiten werden immunmodulatorische Medikamente eingesetzt, etwa TNF-alpha-Blocker (z.B. Etanercept) im Falle der RA und IFN-beta-Präparate (z.B. Betaferon und Avonex) im Falle der MS. Bis heute sind die molekularen Mechanismen dieser Therapien weitestgehend unbekannt. Zudem ist ihre Wirksamkeit und Verträglichkeit bei einigen Patienten unzureichend. In dieser Arbeit wurde die transkriptionelle Antwort im Blut von Patienten auf jede dieser drei Therapien untersucht, um die Wirkungsweise dieser Medikamente besser zu verstehen. Dabei wurden Methoden der Netzwerkinferenz eingesetzt, mit dem Ziel, die genregulatorischen Netzwerke (GRNs) der in ihrer Expression veränderten Gene zu rekonstruieren. Ausgangspunkt dieser Analysen war jeweils ein Genexpressions- Datensatz. Daraus wurden zunächst Gene gefiltert, die nach Therapiebeginn hoch- oder herunterreguliert sind. Anschließend wurden die genregulatorischen Regionen dieser Gene auf Transkriptionsfaktor-Bindestellen (TFBS) analysiert. Um schließlich GRN-Modelle abzuleiten, wurde ein neuer Netzwerkinferenz-Algorithmus (TILAR) verwendet. TILAR unterscheidet zwischen Genen und TF und beschreibt die regulatorischen Effekte zwischen diesen durch ein lineares Gleichungssystem. TILAR erlaubt dabei Vorwissen über Gen-TF- und TF-Gen-Interaktionen einzubeziehen. Im Ergebnis wurden komplexe Netzwerkstrukturen rekonstruiert, welche die regulatorischen Beziehungen zwischen den Genen beschreiben, die im Verlauf der Therapien differentiell exprimiert sind. Für die Etanercept-Therapie wurde ein Teilnetz gefunden, das Gene enthält, die niedrigere Expressionslevel bei RA-Patienten zeigen, die sehr gut auf das Medikament ansprechen. Die Analyse von GRNs kann somit zu einem besseren Verständnis Therapie-assoziierter Prozesse beitragen und transkriptionelle Unterschiede zwischen Patienten aufzeigen

Pattern Recognition

A wealth of advanced pattern recognition algorithms are emerging from the interdiscipline between technologies of effective visual features and the human-brain cognition process. Effective visual features are made possible through the rapid developments in appropriate sensor equipments, novel filter designs, and viable information processing architectures. While the understanding of human-brain cognition process broadens the way in which the computer can perform pattern recognition tasks. The present book is intended to collect representative researches around the globe focusing on low-level vision, filter design, features and image descriptors, data mining and analysis, and biologically inspired algorithms. The 27 chapters coved in this book disclose recent advances and new ideas in promoting the techniques, technology and applications of pattern recognition

Computational Intelligence Sequential Monte Carlos for Recursive Bayesian Estimation

Recursive Bayesian estimation using sequential Monte Carlos methods is a powerful numerical technique to understand latent dynamics of non-linear non-Gaussian dynamical systems. Classical sequential Monte Carlos suffer from weight degeneracy which is where the number of distinct particles collapse. Traditionally this is addressed by resampling, which effectively replaces high weight particles with many particles with high inter-particle correlation. Frequent resampling, however, leads to a lack of diversity amongst the particle set in a problem known as sample impoverishment. Traditional sequential Monte Carlo methods attempt to resolve this correlated problem however introduce further data processing issues leading to minimal to comparable performance improvements over the sequential Monte Carlo particle filter. A new method, the adaptive path particle filter, is proposed for recursive Bayesian estimation of non-linear non-Gaussian dynamical systems. Our method addresses the weight degeneracy and sample impoverishment problem by embedding a computational intelligence step of adaptive path switching between generations based on maximal likelihood as a fitness function. Preliminary tests on a scalar estimation problem with non-linear non-Gaussian dynamics and a non-stationary observation model and the traditional univariate stochastic volatility problem are presented. Building on these preliminary results, we evaluate our adaptive path particle filter on the stochastic volatility estimation problem. We calibrate the Heston stochastic volatility model employing a Markov chain Monte Carlo on six securities. Finally, we investigate the efficacy of sequential Monte Carlos for recursive Bayesian estimation of astrophysical time series. We posit latent dynamics for both regularized and irregular astrophysical time series, calibrating fifty-five quasar time series using the CAR(1) model. We find the adaptive path particle filter to statistically significantly outperform the standard sequential importance resampling particle filter, the Markov chain Monte Carlo particle filter and, upon Heston model estimation, the particle learning algorithm particle filter. In addition, from our quasar MCMC calibration we find the characteristic timescale τ to be first-order stable in contradiction to the literature though indicative of a unified underlying structure. We offer detailed analysis throughout, and conclude with a discussion and suggestions for future work

A layered control architecture for mobile robot navigation

A Thesis submitted to the University Research Degree Committee in fulfillment ofthe requirements for the degree of DOCTOR OF PHILOSOPHY in RoboticsThis thesis addresses the problem of how to control an autonomous mobile robot navigation in indoor environments, in the face of sensor noise, imprecise information, uncertainty and limited response time. The thesis argues that the effective control of autonomous mobile robots can be achieved by organising low level and higher level control activities into a layered architecture. The low level reactive control allows the robot to respond to contingencies quickly. The higher level control allows the robot to make longer term decisions and arranges appropriate sequences for a task execution. The thesis describes the design and implementation of a two layer control architecture, a task template based sequencing layer and a fuzzy behaviour based low level control layer. The sequencing layer works at the pace of the higher level of abstraction, interprets a task plan, mediates and monitors the controlling activities. While the low level performs fast computation in response to dynamic changes in the real world and carries out robust control under uncertainty. The organisation and fusion of fuzzy behaviours are described extensively for the construction of a low level control system. A learning methodology is also developed to systematically learn fuzzy behaviours and the behaviour selection network and therefore solve the difficulties in configuring the low level control layer. A two layer control system has been implemented and used to control a simulated mobile robot performing two tasks in simulated indoor environments. The effectiveness of the layered control and learning methodology is demonstrated through the traces of controlling activities at the two different levels. The results also show a general design methodology that the high level should be used to guide the robot's actions while the low level takes care of detailed control in the face of sensor noise and environment uncertainty in real time

Computational intelligence approaches to robotics, automation, and control [Volume guest editors]

No abstract available