Attribute Exploration of Gene Regulatory Processes

This thesis aims at the logical analysis of discrete processes, in particular of such generated by gene regulatory networks. States, transitions and operators from temporal logics are expressed in the language of Formal Concept Analysis. By the attribute exploration algorithm, an expert or a computer program is enabled to validate a minimal and complete set of implications, e.g. by comparison of predictions derived from literature with observed data. Here, these rules represent temporal dependencies within gene regulatory networks including coexpression of genes, reachability of states, invariants or possible causal relationships. This new approach is embedded into the theory of universal coalgebras, particularly automata, Kripke structures and Labelled Transition Systems. A comparison with the temporal expressivity of Description Logics is made. The main theoretical results concern the integration of background knowledge into the successive exploration of the defined data structures (formal contexts). Applying the method a Boolean network from literature modelling sporulation of Bacillus subtilis is examined. Finally, we developed an asynchronous Boolean network for extracellular matrix formation and destruction in the context of rheumatoid arthritis.Comment: 111 pages, 9 figures, file size 2.1 MB, PhD thesis University of Jena, Germany, Faculty of Mathematics and Computer Science, 2011. Online available at http://www.db-thueringen.de/servlets/DocumentServlet?id=1960

The role of acidity in tumour development

Acidic pH is a common characteristic of human tumours. It has a significant impact on tumour progression and response to therapies. In this thesis, we utilise mathematical modelling to examine the role of acidosis in the interaction between normal and tumour cell populations. In the first section we investigate the cell–microenvironmental interactions that mediate somatic evolution of cancer cells. The model predicts that selective forces in premalignant lesions act to favour cells whose metabolism is best suited to respond to local changes in oxygen, glucose and pH levels. In particular the emergent cellular phenotype, displaying increased acid production and resistance to acid-induced toxicity, has a significant proliferative advantage because it will consistently acidify the local environment in a way that is toxic to its competitors but harmless to itself. In the second section we analyse the role of acidity in tumour growth. Both vascular and avascular tumour dynamics are investigated, and a number of different behaviours are observed. Whilst an avascular tumour always proceeds to a benign steady state, a vascular tumour may display either benign or invasive dynamics, depending on the value of a critical parameter. Extensions of the model show that cellular quiescence, or non-proliferation, may provide an explanation for experimentally observed cycles of acidity within tumour tissue. Analysis of both models allows assessment of novel therapies directed towards changing the level of acidity within the tumour. Finally we undertake a comparison between experimental tumour pH images and the models of acid dynamics set out in previous chapters. This analysis will allow us to assess and verify the previous modelling work, giving the mathematics a firm biological foundation. Moreover, it provides a methodology of calculating important diagnostic parameters from pH images

Computation with photochromic memory

Unconventional computing is an area of research in which novel materials and paradigms are utilised to implement computation and data storage. This includes attempts to embed computation into biological systems, which could allow the observation and modification of living processes. This thesis explores the storage and computational capabilities of a biocompatible light-sensitive (photochromic) molecular switch (NitroBIPS) that has the potential to be embedded into both natural and synthetic biological systems. To achieve this, NitroBIPS was embedded in a (PDMS) polymer matrix and an optomechanical setup was built in order to expose the sample to optical stimulation and record fluorescent emission. NitroBIPS has two stable forms - one fluorescent and one non-fluorescent - and can be switched between the two via illumination with ultraviolet or visible light. By exposing NitroBIPS samples to specific stimulus pulse sequences and recording the intensity of fluorescence emission, data could be stored in registers and logic gates and circuits implemented. In addition, by moving the area of illumination, sub-regions of the sample could be addressed. This enabled parallel registers, Turing machine tapes and elementary cellular automata to be implemented. It has been demonstrated, therefore, that photochromic molecular memory can be used to implement conventional universal computation in an unconventional manner. Furthermore, because registers, Turing machine tapes, logic gates, logic circuits and elementary cellular automata all utilise the same samples and same hardware, it has been shown that photochromic computational devices can be dynamically repurposed. NitroBIPS and related molecules have been shown elsewhere to be capable of modifying many biological processes. This includes inhibiting protein binding, perturbing lipid membranes and binding to DNA in a manner that is dependent on the molecule's form. The implementation of universal computation demonstrated in this thesis could, therefore, be used in combination with these biological manipulations as key components within synthetic biology systems or in order to monitor and control natural biological processes

91st Annual Meeting of the Virginia Academy of Science: Proceedings

Proceedings of the 91st Annual Meeting of the Virginia Academy of Science, held at Virginia Polytechnic Institute and State University, May 22-24, 2013

Computation with photochromic memory

Unconventional computing is an area of research in which novel materials and paradigms are utilised to implement computation and data storage. This includes attempts to embed computation into biological systems, which could allow the observation and modification of living processes. This thesis explores the storage and computational capabilities of a biocompatible light-sensitive (photochromic) molecular switch (NitroBIPS) that has the potential to be embedded into both natural and synthetic biological systems. To achieve this, NitroBIPS was embedded in a (PDMS) polymer matrix and an optomechanical setup was built in order to expose the sample to optical stimulation and record fluorescent emission. NitroBIPS has two stable forms - one fluorescent and one non-fluorescent - and can be switched between the two via illumination with ultraviolet or visible light. By exposing NitroBIPS samples to specific stimulus pulse sequences and recording the intensity of fluorescence emission, data could be stored in registers and logic gates and circuits implemented. In addition, by moving the area of illumination, sub-regions of the sample could be addressed. This enabled parallel registers, Turing machine tapes and elementary cellular automata to be implemented. It has been demonstrated, therefore, that photochromic molecular memory can be used to implement conventional universal computation in an unconventional manner. Furthermore, because registers, Turing machine tapes, logic gates, logic circuits and elementary cellular automata all utilise the same samples and same hardware, it has been shown that photochromic computational devices can be dynamically repurposed. NitroBIPS and related molecules have been shown elsewhere to be capable of modifying many biological processes. This includes inhibiting protein binding, perturbing lipid membranes and binding to DNA in a manner that is dependent on the molecule's form. The implementation of universal computation demonstrated in this thesis could, therefore, be used in combination with these biological manipulations as key components within synthetic biology systems or in order to monitor and control natural biological processes

Insights into the Role of Chemokines, Damage-Associated Molecular Patterns, and Lymphocyte-Derived Mediators from Computational Models of Trauma-Induced Inflammation

Significance: Traumatic injury elicits a complex, dynamic, multidimensional inflammatory response that is intertwined with complications such as multiple organ dysfunction and nosocomial infection. The complex interplay between inflammation and physiology in critical illness remains a challenge for translational research, including the extrapolation to human disease from animal models. Recent Advances: Over the past decade, we and others have attempted to decipher the biocomplexity of inflammation in these settings of acute illness, using computational models to improve clinical translation. In silico modeling has been suggested as a computationally based framework for integrating data derived from basic biology experiments as well as preclinical and clinical studies. Critical Issues: Extensive studies in cells, mice, and human blunt trauma patients have led us to suggest (i) that while an adequate level of inflammation is required for healing post-trauma, inflammation can be harmful when it becomes self-sustaining via a damage-associated molecular pattern/Toll-like receptor-driven feed-forward circuit; (ii) that chemokines play a central regulatory role in driving either self-resolving or self-maintaining inflammation that drives the early activation of both classical innate and more recently recognized lymphoid pathways; and (iii) the presence of multiple thresholds and feedback loops, which could significantly affect the propagation of inflammation across multiple body compartments. Future Directions: These insights from data-driven models into the primary drivers and interconnected networks of inflammation have been used to generate mechanistic computational models. Together, these models may be used to gain basic insights as well as serving to help define novel biomarkers and therapeutic targets. Antioxid. Redox Signal. 23, 1370?1387.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/140310/1/ars.2015.6398.pd

【研究分野別】シーズ集 [英語版]

[英語版

Aging and Health

Aging is a major risk factor for chronic diseases, which in turn can provide information about the aging of a biological system. This publication serves as an introduction to systems biology and its application to biological aging. Key pathways and processes that impinge on aging are reviewed, and how they contribute to health and disease during aging is discussed. The evolution of this situation is analyzed, and the consequences for the study of genetic effects on aging are presented. Epigenetic programming of aging, as a continuation of development, creates an interface between the genome and the environment. New research into the gut microbiome describes how this interface may operate in practice with marked consequences for a variety of disorders. This analysis is bolstered by a view of the aging organism as a whole, with conclusions about the mechanisms underlying resilience of the organism to change, and is expanded with a discussion of circadian rhythms in aging