When the German chemist Emil Fischer presented his key-lock hypothesis in 1899, his analogy to describe the molecular relationship between enzymes and substrates quickly gained vast influence and provided future generations of scientists with a tool to investigate the relation between chemical structure and biological specificity. Rebecca Mertens explains the appeal of the lock-and-key analogy by its role in model building and in the construction of long-term, cross-generational research programs. She argues that a crucial feature of these research programs, namely ascertaining the continuity of core ideas and concepts, is provided by a certain way of analogy-based modeling.
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• General introduction.- Discovery of human microRNA precursor binding to folic acid by small RNA transcriptomic SELEX.- Orthogonal ribosome-tRNAs pair by engineering of peptidyl transferase center.- General conclusion.
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In this thesis, applications of aminoacylation ribozymes named flexizymes are described. Flexizymes have the following unique characteristics: (i) substrate RNA is recognized by two consecutive base pairs between the 3'-end of substrate RNA and the 3'-end of the flexizyme; (ii) these base pairs can be substituted with other base pairs; and (iii) various activated amino acids can be used as substrates including both canonical and noncanonical amino acids. This flexible aminoacylation of RNAs by flexizymes was used to label endogenous tRNAs to be removed, and in vitro selection using the tRNA-depleted library enabled the discovery of the novel interaction between the microRNA precursor and metabolites. Flexizymes are also used to prepare various aminoacyl-tRNAs bearing mutations at the 3'-end to engineer the translation machinery and to develop the orthogonal translation machinery. The first part of the research demonstrated that SELEX is appropriate for discovering the interaction between small RNA and ligands, and suggested that more RNA motif binding to small molecules exists in small RNAs. The second part opened a door to new opportunities for in vitro synthetic biology involving the engineering of the genetic codes and translation machineries. This research also indicated the great potential of aminoacylation by flexizymes to be applied in various fields of RNA research, which is beneficial for RNA researchers.
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• Introduction.- Online sample injection and multidimensional chromatography separation by using strong cation exchange monolithic column.- Development of polymer-based hydrophobic monolithic columns and their applications in proteome analysis.- Large-scale proteome and phosphoproteome quantification by using dimethylation isotope labeling.
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In this thesis, the author outlines the development of new monolithic columns and isotope dimethyl labeling strategies and their applications in high-performance proteome analyses. Though different types of monolithic columns have been widely developed for chromatography and electrophoresis separation, their application in proteomics for complex peptide mixtures separation is still a challenge. The author discusses the preparation of new monolithic columns and optimization of chromatography separation capability to improve coverage and accuracy of proteome analysis. Further, the author describes a novel online multidimensional chromatography system combined with automated online isotope labeling, which significantly improves the throughput, sensitivity and accuracy of quantitative proteomics. In addition to the development of new technologies, the author investigates the proteome and phosphoproteome expression changes of clinical hepatocellular carcinoma tissues and the hippocampi of mice with Alzheimer's disease. The work in this thesis has led to several publications in high-profile journals in the fields of analytical chemistry and proteome research.
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• Introduction.- Computational analysis of PAR-CLIP data.- Transcriptome-wide analysis of regulatory interactions of the RNA-binding protein HuR.- Binding site occupancy with competition interactions in equilibrium.- Circular RNAs are a large class of animal RNAs with regulatory potency.- Discussion.- Methods.
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The work described in this book is an excellent example of interdisciplinary research in systems biology. It shows how concepts and approaches from the field of physics can be efficiently used to answer biological questions and reports on a novel methodology involving creative computer-based analyses of high-throughput biological data. Many of the findings described in the book, which are the result of collaborations between the author (a theoretical scientist) and experimental biologists and between different laboratories, have been published in high-quality peer-reviewed journals such as Molecular Cell and Nature. However, while those publications address different aspects of post-transcriptional gene regulation, this book provides readers with a complete, coherent and logical view of the research project as a whole. The introduction presents post-transcriptional gene regulation from a distinct angle, highlighting aspects of information theory and evolution and laying the groundwork for the questions addressed in the subsequent chapters, which concern the regulation of the transcriptome as the primary functional carrier of active genetic information.
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• Introduction: Bottom-Up Methodology for Integrating Synthetic Double Helix Molecules Via Self-Assembly Process
• Synthesis of Ethynylhelicene Oligomers
• Homo-Double-Helix Formation of Ethynylhelicene Oligomers Possessing Various Side Chains
• Hetero-Double-Helix Formation of Pseudoenantiomeric Ethynylhelicene Oligomers
• Higher-Assembly Formation of Pseudoenantiomeric Ethynylhelicene Oligomers
• Conclusions
• Experimental Section.

In biological systems, molecules hierarchically form ordered assemblies and macroscopic substances, as exemplified by the assembly of proteins. The development of such systems using oligomeric macromolecules obtained by organic synthesis can provide insights into biological phenomena and will lead to the creation of new materials. In this regard, synthetic double helix molecules are attractive subjects of study because they have an important structural motif that appears widely in nature and can exhibit dynamic structural change. This thesis describes an unprecedented bottom-up approach using synthetic ethynylhelicene oligomers, which form dynamic double helices in organic media. Oligomer synthesis, homo- and hetero-double helix formation, and higher assembly formation due to intercomplex interactions are documented. The hierarchical assembly formation is a cogent reminder of the assembly of biological proteins that create living creatures. Also notable here is the demonstration of a methodology of providing diverse hetero-double helices and their higher assemblies by changing the combination of oligomers, which can be another advantage of this synthetic system.

• Introduction
• Concept and State-of-the-Art
• Results and Discussion
• Conclusion
• Materials and Methods.

Christopher Schirwitz's thesis focuses on improving the quality of in situ synthesized high-complexity peptide micro arrays. Micro arrays containing proteins or small protein fragments in the form of peptides have become of great interest in proteomic research. With the help of these microarrays a large number of potential target molecules can be screened for interaction with a probe in a short timeframe. However, protein and peptide micro arrays are still lagging behind oligonucleotide arrays in terms of density, quality and manufacturing costs. A new approach developed at the German Cancer Research Center (DKFZ) has improved the synthesis of high-density peptide arrays. The current technology is capable of producing arrays with up to 40,000 different peptides per square cm by means of micro particle-based solid phase peptide synthesis. However, in situ synthesis approaches bear a conceptual disadvantage: The quality of the peptides is dependent on the efficiency of the synthesis so that peptide fragments are present in the resulting array among the desired full-length peptides. In peptide-protein interaction studies such peptide fragments. The central achievement of this thesis is the development of a new method allowing for the fast one-step purification of entire arrays without loss of resolution or spatial information. Christopher Schirwitz's work has resulted in a number of publications in high ranking journals.

• Introduction
• A Novel DNA Model
• Methods
• Finite Size Effects
• Stuctural and Mechanical Properties of Model DNA
• Thermodynamic Properties of Model DNA
• Modelling DNA Tweezers
• Modelling a DNA Walker
• Conclusions.

This thesis presents a novel coarse-grained model of DNA, in which bases are represented as rigid nucleotides. The model is shown to quantitatively reproduce many phenomena, including elastic properties of the double-stranded state, hairpin formation in single strands and hybridization of pairs of strands to form duplexes, the first time such a wide range of properties has been captured by a coarse-grained model. The scope and potential of the model is demonstrated by simulating DNA tweezers, an iconic nanodevice, and a two-footed DNA walker -- the first time that coarse-grained modelling has been applied to dynamic DNA nanotechnology.

• Introduction
• Theoretical Methods of Quantum Mechanics
• Degrees of Freedom in Polypeptides and Proteins
• Partition Function of a Polypeptide
• Phase Transitions in Polypeptides
• Folding of Proteins in Aqueous Environment.

There are nearly 100 000 different protein sequences encoded in the human genome, each with its own specific fold. Understanding how a newly formed polypeptide sequence finds its way to the correct fold is one of the greatest challenges in the modern structural biology. The aim of this thesis is to provide novel insights into protein folding by considering the problem from the point of view of statistical mechanics. The thesis starts by investigating the fundamental degrees of freedom in polypeptides that are responsible for the conformational transitions. This knowledge is then applied in the statistical mechanics description of helix-coil transitions in polypeptides. Finally, the theoretical formalism is generalized to the case of proteins in an aqueous environment. The major novelty of this work lies in combining (a) a formalism based on fundamental physical properties of the system and (b) the resulting possibility of describing the folding-unfolding transitions quantitatively. The clear physical nature of the formalism opens the way to further applications in a large variety of systems and processes.

• Modulation Threshold and Noise
• Model for the Spatial Contrast Sensitivity of the Eye
• Extension of the Contrast Sensitivity Model to Extra-Foveal Vision
• Extension of the Contrast Sensitivity Model to the Temporal Domain
• Effect of Nonwhite Spatial Noise on Contrast Sensitivity
• Contrast Discrimination Model
• Image Quality Measure
• Effect of Various Parameters on Image Quality.
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This book examines the contrast sensitivity of the human visual system - concerning the eye's ability to distinguish objects from each other or from the background - and its effects on the imageforming process. The text provides equations for determining various aspects of contrast sensitivity, in addition to models that easily can be used for practical applications.
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