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Inverarity, Iain Andrew. "Marked small molecule libraries : a new approach to molecular probe design." Thesis, University of Edinburgh, 2007. http://hdl.handle.net/1842/14147.
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This thesis documents a new approach for the identification of a small biologically active molecule’s site of interaction, through the rapid synthesis of molecular probes. A marked library approach has been developed whereby a biocompatible marker is attached onto the small molecule’s molecular scaffold. This marker plays no role in the screening process itself, but facilitates the formation of a range of molecular probes from active marked library members. As an example of molecular probe formation, site selective biotinylation will be discussed in the introduction. This marked library concept has been applied to the natural product anisomycin A. Investigations focused on development of a detailed structure activity relationship for anisomycin’s activation of the stress activated protein kinase (SAPK) pathway, along with the synthesis of a number of marked library analogues. The active marked library members were then converted to a range of functional molecular probes utilising the copper(I) catalysed Huisgen cycloaddition as the key coupling step. These molecular probes are being used in the elucidation of anisomycin’s biological target for activation of the SAPK pathway. In a further demonstration of this strategy, a focused library of marked steroids has been synthesised based on the functionalisation of dehydroepiandrosterone B. Directed by the results of preliminary biological screening, a number of marked library members have been converted into fluorescent molecular probes. These probes will be used in future applications to probe the biological action of the dehydroepiandrosterone.
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Forshaw, Paula Louise. "Kinetic studies of probe molecule adsorption on activated carbons." Thesis, University of Newcastle Upon Tyne, 2000. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.324940.
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Taylor, Christopher George. "Novel fluorescence techniques to probe protein aggregation." Thesis, University of Cambridge, 2018. https://www.repository.cam.ac.uk/handle/1810/276197.
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The self-assembly of amyloidogenic proteins to form cytotoxic species that give rise to brain deterioration underlies numerous neurodegenerative disorders such as Alzheimer’s and Parkinson’s diseases. Increasing evidence indicates that it is the rare, low-molecular-weight species (oligomers) rather than the more abundant high-molecular-weight fibrils of certain proteins that are the most cytotoxic in several neurodegenerative diseases. However, these species have proven difficult to study using traditional methods due to their transient nature and the heterogeneity of aggregation mixtures. In this thesis, I describe my work to develop advanced methods where I combine single-molecule and ensemble fluorescence techniques with microfluidic strategies to enable the study of protein aggregation, spanning small, transient oligomers to large, insoluble aggregates. In Chapter 1 I give an overview of the biological context and relevance of this work, including the background of neurodegenerative disease, amyloidogenic aggregation and key proteins involved. I then briefly review fluorescence microscopy techniques and the field of microfluidics. In Chapter 2 I describe how complex microfluidics can be integrated with single-molecule confocal techniques to provide a highly sensitive method to continuously probe protein aggregation in vitro. I show, for the first time, that the dilution of aggregating mixtures may be automated, by up to five orders of magnitude, down to the picomolar concentrations suitable for single-molecule measurements. By incorporating this microfluidic dilution device I greatly improve the temporal resolution of the technique and facilitate the observation of more transient species through the ability to rapidly dilute and take fluorescence measurements of samples. In Chapter 3 I overcome the need for in situ labels to monitor amyloidogenic aggregation using single-molecule confocal microscopy. I describe my work to adapt the single-molecule confocal technique to achieve the ultrasensitive detection of individual aggregate species under flow without covalently-attached labels. I have demonstrated the ability of this new method to monitor the aggregation of label-free amyloidogenic proteins using extrinsic labels ex-aggregation, opening the way for biological samples to be probed in a high-throughput manner. In Chapter 4 I describe my work to combine the high precision of confocal microscopy with a microfluidic device developed to directly characterise the sizes and interactions of biomolecules in the continuous phase. By monitoring the spatial and temporal mass transport on the micron scale, the diffusion coefficient, and thus hydrodynamic radius, of species may be determined. The technique delivers much greater sensitivity for size quantification, allowing scarce and other challenging samples to be characterised, and provides significant steps towards accurate sizing for single-molecule aggregation experiments under flow. In Chapter 5 I describe my work to determine the microscopic driving force for the spatial propagation of amyloid-beta. The epifluorescence instrument I built has enabled the proliferation of aggregate species to be monitored over a macro distance on a timescale of minutes. This has greatly improved the scope of the experimental data attained, which will be used in conjunction with Monte Carlo simulations to deliver a model for the propagation of amyloid-beta in vitro. Together this thesis represents my work developing the above novel fluorescence techniques to improve their temporal and size resolution, sensitivity and adaptability to study highly complex and fundamental protein aggregation linked to neurodegenerative disease.
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Adhikari, Subhasis, and Frank Cichos. "Probe size dependent rotational dynamics in polymer by single molecule spectroscopy." Universitätsbibliothek Leipzig, 2015. http://nbn-resolving.de/urn:nbn:de:bsz:15-qucosa-185732.
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Pawlosky, Annalisa M. (Annalisa Marie). "Single molecule techniques to probe decision-making processes in developmental biology." Thesis, Massachusetts Institute of Technology, 2014. http://hdl.handle.net/1721.1/87503.
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Thesis: Ph. D., Harvard-MIT Program in Health Sciences and Technology, 2014.Cataloged from PDF version of thesis.
Includes bibliographical references.
This work investigates the fundamental processes used by mammalian cells and organisms to make decisions during embryonic development. Current technologies that evaluate biological phenomenon often force a compromise between quantification of gene expression via bulk assays and qualitative imaging of cell and tissue heterogeneity. There are few options that allow for quantitative, high-resolution, single-cell analysis that is robust but not associated with a high degree of technical difficulty or obscured by amplification. Here, we address these issues using two model systems, the developing mammalian inner ear and single mouse embryonic stem cells (mESCs) during the process of X inactivation, to demonstrate our ability to perform single-cell, single-molecule assays that reveal both highly quantitative and spatial information. Accordingly, we adapted a high resolution, single-molecule RNA fluorescent in situ hybridization technique (smFISH) to study gene expression in the inner ear and perform allele-specific detection of the X chromosome in mESCs. We used previously-published smFISH procedures as our initial template for investigating biological signaling phenomena in these two systems. To study gene expression in the mouse inner ear, we developed a modified smFISH strategy to investigate mRNA transcript expression patterns in the cochlea during auditory hair cell development. The mammalian cochlea, a highly specialized and complex organ, beautifully demonstrates both the depth and breadth of the smFISH technique. To assay signaling behavior and topological changes of the X chromosome prior to X inactivation, we incorporated a novel allele-specific modification into the smFISH technique. We investigate the allele-specific expression patterns of eight genes that tile the X chromosome, which were chosen for their varied putative roles before, during and after X chromosome inactivation. Taken together, these two systems recapitulate the strength of the smFISH technique and its adaptations. The goals of this thesis were twofold: (1) expand the smFISH technique to work in specialized mammalian systems such as the cochlea and (2) demonstrate allele-specific DNA topological changes and expression patterns in mESCs. Elucidating high-resolution, single-molecule quantifiable imaging methods for application to complex tissues or allele-specific probing will have profound impacts on future investigations and promote a deeper comprehension of these systems.
by Annalisa M. Pawlosky.
Ph. D.
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Adhikari, Subhasis, and Frank Cichos. "Probe size dependent rotational dynamics in polymer by single molecule spectroscopy." Diffusion fundamentals 16 (2011) 77, S. 1-2, 2011. https://ul.qucosa.de/id/qucosa%3A13821.
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Egleton, James Edward. "Small molecule colorimetric and fluorescent probes for specific protein detection." Thesis, University of Oxford, 2015. http://ora.ox.ac.uk/objects/uuid:0a1a1c80-8055-491a-920a-3e17f7919e93.
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This thesis describes the design, synthesis, analysis, mechanistic evaluation and optimisation of small molecule probes for the specific detection of proteins, focusing on the target protein human arylamine N-acetyltransferase type 1 (HUMAN(NAT1)) and its murine homologue, mouse arylamine N-acetyltransferase type 2 (MOUSE(NAT2)). The HUMAN(NAT1) gene is reported to be one of the most highly overexpressed genes in estrogen-receptor-positive (ER+) breast tumours, leading to its potential use as both a novel diagnostic biomarker and a novel therapeutic target for this disease. Chapter 1 reviews the literature on optical methods for the specific detection of a protein target, exploring strategies both based on biosensors and on chemical probes, before introducing the arylamine N-acetyltransferases as a family of enzymes. In Chapter 2, a family of naphthoquinone inhibitors of HUMAN(NAT1) are introduced, which undergo a colour change from red to blue upon binding specifically to the enzyme. The mechanism of this colour change, a proton transfer-mediated process, is discussed via the synthesis, pharmacological and colorimetric evaluation of close analogues of the hit compound lacking a key acidic sulfonamide-NH proton. During these studies, it was found that direct O-methylation of a sulfonamide is possible under certain conditions; such a reaction has not previously been reported. Furthermore, upon heating in polar solvents the O-methylated sulfonamide was observed to undergo rearrangement, and the mechanism of this process is investigated via NMR and kinetic studies. In Chapter 3, the design, synthesis and evaluation of HUMAN(NAT1) inhibitors with improved pharmacological and colorimetric profiles over the initial hit are described. From this optimisation, structure-activity relationships and an in silico model of interactions between the inhibitors and enzyme are evaluated. Testing of these compounds in cellular environments, however, exposes some limitations of this approach, notably the lack of sensitivity of the probes when dosed at low concentrations in cellular samples. In order to overcome this limitation, in Chapter 4 fluorescent analogues of the hit compound are designed and synthesised. Initial compounds developed in this series possess promising properties, but each compound generated suffers from either a low fluorescent intensity, lack of a pH-dependent switch in fluorescence or a low fluorescence excitation wavelength, which overlaps with those of tryptophan or tyrosine residues in proteins. Insights into the mechanism of molecular fluorescence and application of some simple quantum mechanical principles, however, lead to the design of a species which possesses all the required properties. The fluorescent emission intensity of this probe correlates linearly with [MOUSE(NAT2)] in E. coli cell extracts, and can quantify as little as 0.64% MOUSE(NAT2) in the samples; furthermore, the probe is capable of unambiguously detecting HUMAN(NAT1) within a cell extract from the ER+ breast cancer cell line ZR-75-1; future work on this probe may therefore enable its clinical use in improved early diagnosis of breast tumours. This study also represents, to the best of our knowledge, the first ever example of a small molecule, non-covalent probe capable of quantifying the concentration of a target protein in cellular extracts. In Chapter 5, the series of naphthoquinone probes is further optimised in order to study the roles of HUMAN(NAT1) in a cellular environment. Firstly, structure-activity relationships are utilised to design inhibitors with improved physical properties such as aqueous solubility and cell membrane permeability, in order to test the effect of HUMAN(NAT1) inhibitors in tumour cell models, which could have implications for the future use of a HUMAN(NAT1) inhibitor as a therapeutic agent in oncology. Secondly, the effect of the cofactor folic acid on the function and activity of HUMAN(NAT1) is explored. Finally, in Chapter 6, the conclusions of this study are outlined and a hypothesis as to how the concepts developed in this thesis might be applied to alternative, more ubiquitous biological targets is discussed, paving the way for future investigations.
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Chen, Changsheng Verfasser], and Maximilian [Akademischer Betreuer] [Ulbrich. "Fluorescently labeled DNA probe in STORM imaging and single-molecule protein labeling." Freiburg : Universität, 2019. http://d-nb.info/1187658545/34.
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Chen, Changsheng [Verfasser], and Maximilian [Akademischer Betreuer] Ulbrich. "Fluorescently labeled DNA probe in STORM imaging and single-molecule protein labeling." Freiburg : Universität, 2019. http://d-nb.info/1187658545/34.
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Ericsson, Olle. "Biomolecular Analysis by Dual-Tag Microarrays and Single Molecule Amplification." Doctoral thesis, Uppsala : Acta Universitatis Upsaliensis : Universitetsbiblioteket [distributör], 2008. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-8475.
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Cross, Stephen John. "Combining magnetic tweezers and single-molecule fluorescence microscopy to probe transcription-coupled DNA supercoiling." Thesis, University of York, 2013. http://etheses.whiterose.ac.uk/4998/.
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Previous studies have shown that translocation of an actively transcribing RNA polymerase leads to local increases or decreases in DNA torsion (twin-supercoiled domain), which cannot be resolved in vivo due to interactions of the template DNA, nascent RNA and polymerase with the crowded cellular environment. Local changes in DNA supercoiling are biologically relevant as they have been shown to regulate transcription initiation at promoters located downstream. Current in vitro single-molecule approaches are not able to directly probe transcription-coupled DNA supercoiling due to an inability to simultaneously monitor changes in torsional stress and localise individual transcribing RNA polymerase(s) on the DNA. Described here is a novel optical microscope, which utilises a combination of magnetic tweezers, bright-field illumination and wide-field epifluorescence imaging to permit the visualisation of fluorescently tagged polymerases transcribing in real-time on a torsionally constrained DNA template. With this unique geometry, transcription as a function of applied torsion can be probed directly in vitro. Unlike standard magnetic tweezers configurations this system extends tethers horizontally relative to the microscope slide surface, which allows individual enzymes to be directly viewed via attached fluorophores. The magnetic tweezers allow both the relative extension and linking number of the DNA tether to be manipulated, thus enabling transcription to be studied under conditions of constant DNA extension and defined torsional stress.
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Brooks, John Daniel. "Model Chromia Surface Chemistry: C2 Alkyl Fragment Reactions and Probe Molecule Interactions." Diss., Virginia Tech, 2010. http://hdl.handle.net/10919/29161.
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The thermally induced reaction of chlorinated ethanes on the nearly-stoichiometric α-Cr₂O₃ (102) surface results in the formation of gas phase hydrocarbons including ethylene, ethane, acetylene, 2-butene, 2-butyne and dihydrogen, and deposition of surface chlorine adatoms. No surface carbon or combustion products are observed in any reactions indicating that no thermally induced C-C bond cleavage occurs and surface lattice oxygen is not incorporated into surface intermediates. A combination of photoemission and Auger electron spectroscopies indicates the surface reactions of the chlorinated ethanes proceed via C-Cl bond cleavage to form surface chlorine adatoms and surface C₂-alkyl hydrocarbon fragments (i.e. ethyl, ethylidene and ethylidyne). Temperature programmed desorption studies indicate that both ethyl and ethylidene intermediates are selective towards ethylene. However, ethylidyne is more selective towards acetylene, but also produces ethylene in significant quantities. Chlorine adatom deposition leads to deactivation of surface Cr reaction centers by simple site blocking.
The interaction of water with nearly-stoichiometric α-Cr₂O₃ (001) and (102) surfaces is structure sensitive. Water is sensitive to the difference in coordination number of Cr surface cations between the two surfaces, and on the α-Cr₂O₃ (001) surface, water has also demonstrated sensitivity to the degree of surface Cr cation reduction (and/or reduced coordination). These observations allowed for the development of a surface treatment recipe for the nearly-stoichiometric (001) surface.Ph. D.
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Orre, Tommy. "Design, synthesis and evaluation of photoaffinity chemical probe to study Lipoprotein lipase – small molecule interactions." Thesis, Umeå universitet, Kemiska institutionen, 2016. http://urn.kb.se/resolve?urn=urn:nbn:se:umu:diva-123298.
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Lee, Peter S. M. Massachusetts Institute of Technology. "Using optical tweezers, single molecule fluorescence and the ZIF268 protein-DNA system to probe mechanotransduction mechanisms." Thesis, Massachusetts Institute of Technology, 2005. http://hdl.handle.net/1721.1/34490.
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Thesis (S.M.)--Massachusetts Institute of Technology, Biological Engineering Division, 2006.Includes bibliographical references (p. 42-43).
Optical tweezers instruments use laser radiation pressure to trap microscopic dielectric beads. With the appropriate chemistry, such a bead can be attached to a single molecule as a handle, permitting the application of force on the single molecule. Measuring the force applied in real-time is dependent on detecting the bead's displacement from the trapping laser beam axis. Back-focal-plane detection provides a way of measuring the displacement, in two-dimensions, at nanometer or better resolution. The first part of this work will describe the design of a simple and inexpensive position sensing module customized for optical tweezers applications. Single molecule fluorescence is another powerful technique used to obtain microscopic details in biological systems. This technique can detect the arrival of a single molecule into a small volume of space or detect the conformational changes of a single molecule. Combining optical tweezers with single-molecule fluorescence so that one can apply forces on a single molecule while monitoring its effects via single molecule fluorescence provides an even more powerful experimental platform to perform such microscopic studies. Due to the enhanced photobleaching of fluorophores caused by the trapping laser, this combined technology has only been demonstrated under optimized conditions.
(cont.) The second part of this work will describe a straightforward and noninvasive method of eliminating this problem. The study of mechanotransduction in biological systems is critical to understanding the coupling between mechanical forces and biochemical reactions. Due to the recent advances in single molecule technology, it is now possible to probe such mechanisms at the single molecule level. The third and final part of this work will describe a basic mechanotransduction experiment using the well-studied ZIF268 protein-DNA system. An experimental assay and method of analysis will be outlined.
by Peter Lee.
S.M.
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Cochrane, Katherine Anne. "Single molecule perspectives of model organic semiconductors : energy level mapping by high-resolution scanning probe microscopy." Thesis, University of British Columbia, 2017. http://hdl.handle.net/2429/62849.
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Organic semiconductors are a promising class of materials for many applications such as photovoltaics, light emitting diodes, and field-effect transistors. As these devices rely on the movement of charge at and near interfaces, understanding energy level alignment at these boundaries is essential to improve device performance. Differences in the local environment and surrounding molecular geometry have the potential to cause significant energy level shifts occurring on single molecule length scales, thus affecting device properties. Scanning Probe Microscopy is a family of techniques that allows investigation of materials on the molecular and submolecular level. Scanning Tunneling Spectroscopy (STS) allows for the mapping of electronic states with spatial and energetic resolution. Electrostatic Force Spectroscopic (EFS) mapping investigates the local charge distribution of surfaces even down to submolecular resolution. We utilize these techniques to investigate the prototypical semiconductors PTCDA and CuPc on NaCl(2ML)/Ag(111).
Nanoislands of PTCDA were examined with STS, revealing strong electronic differences between molecules at the edges and those in the center, with energy level shifts of up to 400 meV. We attribute this to the change in electrostatic environment at the boundaries of clusters, namely via polarization of neighboring molecules. To further investigate the local electrostatics, we use EFS to probe the effect of adding charge to PTCDA molecules, both isolated and within clusters. We found that the charging energy depends on the initial local charge distribution by spatially resolving the charging events with sub-molecular resolution.
In order to investigate the influence of interface geometry, we use pixel-by-pixel STS of the prototypical acceptor/donor system PTCDA/CuPc. We observe shifting of the donor and acceptor states in opposite directions, indicating an equilibrium charge transfer between the two. Further, we find that the spatial location of electronic states of both acceptor and donor is strongly dependent on the relative positioning of both molecules in larger clusters. The observation of these strong shifts illustrates a crucial issue: interfacial energy level alignment can differ substantially from the bulk electronic structure in organic materials. This has significant implications for device design, where energy level alignment strongly correlates to device performance.Science, Faculty of
Chemistry, Department of
Graduate
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Göransson, Jenny. "Readout Strategies for Biomolecular Analyses." Doctoral thesis, Uppsala universitet, Institutionen för genetik och patologi, 2008. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-9343.
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This thesis describes three readout formats for molecular analyses. A common feature in all works is probing techniques that upon specific target recognition ideally results in equimolar amounts of DNA circles. These are then specifically amplified and detected using any of the techniques presented herein. The first paper presents a method that enables homogeneous digital detection and enumeration of biomolecules, represented as fluorescence-labelled DNA macromolecules. This method offers precise measurements to be performed with a wide linear dynamic range. As an application, two closely related bacterial species were selectively detected. The second paper further investigates and optimizes the properties of the technique presented in paper one. The third paper demonstrates a platform that enables simultaneous quantitative analysis of large numbers of biomolecules. The array format and decoding scheme together propose a digital strategy for decoding of biomolecules. The array and the decoding procedure were characterized and evaluated for gene copy-number measurements. The fourth paper examines a new strategy for non-optical measurements of biomolecules. Characteristics of this technique are investigated, and compared to its optical equivalent, fluorescence polarization.
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Lin, Ya. "Single-molecule techniques to probe the dynamic gene regulatory network formed by core pluripotency circuit in embryonic stem cells." Thesis, Harvard University, 2014. http://nrs.harvard.edu/urn-3:HUL.InstRepos:13070085.
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This work investigates the dynamics of gene regulatory network formed by Oct4, Sox2 and Nanog in embryonic stem cells (ESCs). Despite a large number of existing studies on stem cells, current technologies used often force a compromise between quantification of gene expression via bulk measurements and qualitative imaging of cell heterogeneity. There are few options that allow for accurate and quantitative single-cell analysis that is robust yet not associated with a high degree of technical difficulty or obscured by amplification. Here, we adapted a high resolution, single-molecule RNA fluorescent in situ hybridization technique (smFISH) to study gene expression of the core pluripotency circuit upon various types of perturbations such as differentiation, induction or knockdown of one of the three pluripotent factors. We used previously-published smFISH procedures as our initial template for investigating gene regulatory dynamics of the core pluripotency circuit during those perturbation assays. To obtain a more comprehensive picture of the regulatory circuit, we developed a modified smFISH strategy to measure mRNA and protein expression simultaneously in single ESCs. By incorporating a novel modification into the smFISH technique which allows accurate quantification of transcripts that differ by short sequences, we managed to identify a few interesting features of the core pluripotency circuit. Taken together, we demonstrated our ability to perform single-cell, single-molecule assays that reveal highly quantitative information in unprecedented detail.
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Yuan, Yuan. "Small-Molecule Modulators of Pancreatic Ductal Cells: Histone Methyltransferases and \(\beta\)-Cell Transdifferentiation." Thesis, Harvard University, 2012. http://dissertations.umi.com/gsas.harvard:10637.
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Small molecules are important not only for treating human diseases but also for studying disease-related biological processes. This dissertation focuses on the effects of small molecules on pancreatic ductal adenocarcinoma cells. Here, I describe the discovery of two small-molecule tool compounds and their applications for interrogating the biological processes related to two distinct diseases in the human pancreas. First, BRD4770 was identified as a histone methyltransferase inhibitor through a target-based biochemical approach, and was used as a probe to study the function of methyltransferases in cancer cells. Second, BRD7552 was discovered as an inducer of Pdx1 using a cell-based phenotypic screening approach, and was used to induce the expression of Pdx1, a master regulatory transcription factor required for \(\beta\)-cell transdifferentiation. This compound is particularly interesting for the study of type-1 diabetes (T1D). The histone methyltransferase G9a catalyzes methylation of lysine 9 on histone H3, a modification linked to aberrant silencing of tumor-suppressor genes. The second chapter describes the collaborative effort leading to the identification of BRD4770 as a probe to study the function of G9a in human pancreatic cancer cells. BRD4770 induces cellular senescence and inhibits both anchorage-dependent and -independent proliferation in PANC-1 cell line, presumably mediated through ATM-pathway activation. Chapter three describes the study of a natural product gossypol, which significantly enhances the BRD4770 cytotoxicity in p53-mutant cells through autophagic cell death. The up-regulation of BNIP3 might be responsible for the synergistic cell death, suggesting that G9a inhibition may help overcome drug resistance in certain cancer cells. Ectopic overexpression of Pdx1, Ngn3, and MafA can reprogram pancreatic exocrine cells to insulin-producing cells in mice, which sheds light on a new avenue for treating T1D. The fourth chapter focuses on a gene expression-based assay using quantitative real-time PCR technique to screen >60,000 compounds for induction of one or more of these three transcription factors. A novel compound BRD7552 which up-regulated Pdx1 mRNA and protein levels in PANC-1 cells was identified. BRD7552 induces changes of the epigenetic markers within the Pdx1 promoter region consistent with transcriptional activation. Furthermore, BRD7552 partially complements Pdx1 in cell culture, enhancing the expression of insulin induced by the introduction of the three genes in PANC-1 cells. In summary, the central theme of my dissertation is to identify novel bioactive small molecules using different screening approaches, as well as to explore their effects in pancreatic ductal cells.Chemistry and Chemical Biology
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Sperl, Alexander Georg [Verfasser], and Joachim [Akademischer Betreuer] Ullrich. "XUV-IR pump-probe experiments: Exploring nuclear and electronic correlated quantum dynamics in the hydrogen molecule / Alexander Georg Sperl ; Betreuer: Joachim Ullrich." Heidelberg : Universitätsbibliothek Heidelberg, 2013. http://d-nb.info/1177148536/34.
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Wang, Xiaoyang. "Design, Construction and Investigation of Synthetic Devices for Biological Systems." University of Cincinnati / OhioLINK, 2011. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1314041031.
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Klajner, Piotr. "Experimental study of the kinetics of two systems : DNA complexation by the NCp7 protein and probe dynamics in a glassy colloidal suspension." Phd thesis, Université de Strasbourg, 2012. http://tel.archives-ouvertes.fr/tel-00858886.
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In the first part of this thesis, we study the kinetics of the complexation of a double-stranded DNA byNCp7 protein. To do this, we study the evolution of mechanical properties of DNA and its complexation by stretching the DNA/NCp7 complex with a optical trap. We observed that the persistence length of the complex decreases progressively during the complexation. Using astatistical model we describe the evolution of the flexibility of DNA complexed with NCp7. Our main result is that the fraction phi of base pairs that have reacted is not a linear function of time at low phi.We interpret our results assuming that the adsorption of NCp7 on DNA is highly cooperative. In the second chapter, we describe the dynamics of probe particles in a colloidal glassy suspension of Laponite. Laponite is a colloidal discoidal particle of 25 nm in diameter and 0.92 nm thick. We take advantage of evanescent wave microscopy, and follow the movement of fluorescent latex particles.Then we image these particles. We show that for a movement that has a single characteristic time scale, it is simply a linear function of time. We find that, what ever their size, the motion of probe particles can be described by a succession of two dynamic modes, where the fastest mode corresponds to the diffusion of particles in a viscoelastic fluid.
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Magrakvelidze, Maia. "Dissociation dynamics of diatomic molecules in intense fields." Diss., Kansas State University, 2013. http://hdl.handle.net/2097/16739.
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Doctor of PhilosophyDepartment of Physics
Uwe Thumm
We study the dynamics of diatomic molecules (dimers) in intense IR and XUV laser fields theoretically and compare the results with measured data in collaboration with different experimental groups worldwide. The first three chapters of the thesis cover the introduction and the background on solving time-independent and time-dependent Schrödinger equation. The numerical results in this thesis are presented in four chapters, three of which are focused on diatomic molecules in IR fields. The last one concentrates on diatomic molecules in XUV pulses. The study of nuclear dynamics of H[subscript]2 or D[subscript]2 molecules in IR pulses is given in Chapter 4. First, we investigate the optimal laser parameters for observing field-induced bond softening and bond hardening in D[subscript]2[superscript]+. Next, the nuclear dynamics of H[subscript]2[superscript]+ molecular ions in intense laser fields are investigated by analyzing their fragment kinetic-energy release (KER) spectra as a function of the pump-probe delay τ. Lastly, the electron localization is studied for long circularly polarized laser pulses. Chapter 5 covers the dissociation dynamics of O[subscript]2[superscript]+ in an IR laser field. The fragment KER spectra are analyzed as a function of the pump-probe delay τ. Within the Born-Oppenheimer approximation, we calculate ab-initio adiabatic potential-energy curves and their electric dipole couplings, using the quantum chemistry code GAMESS. In Chapter 6, the dissociation dynamics of the noble gas dimer ions He[subscript]2[superscript]+, Ne[subscript]2[superscript]+, Ar[subscript]2[superscript]+, Kr[subscript]2[superscript]+, and Xe[subscript]2[superscript]+ is investigated in ultrashort pump and probe laser pulses of different wavelengths. We observe a striking ‘‘delay gap’’ in the pump-probe-delay-dependent KER spectrum only if the probe-pulse wavelength exceeds the pump-pulse wavelength. Comparing pump-probe-pulse-delay dependent KER spectra for different noble gas dimer cations, we quantitatively discuss quantum-mechanical versus classical aspects of the nuclear vibrational motion as a function of the nuclear mass. Chapter 7 focuses on diatomic molecules in XUV laser pulses. We trace the femtosecond nuclear-wave-packet dynamics in ionic states of oxygen and nitrogen diatomic molecules by comparing measured kinetic-energy-release spectra with classical and quantum-mechanical simulations. Experiments were done at the free-electron laser in Hamburg (FLASH) using 38-eV XUV-pump–XUV-probe. The summary and outlook of the work is discussed in Chapter 8.
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Weibrecht, Irene. "Visualizing Interacting Biomolecules In Situ." Doctoral thesis, Uppsala universitet, Molekylära verktyg, 2011. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-151579.
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Intra- and intercellular information is communicated by posttranslational modifications (PTMs) and protein-protein interactions, transducing information over cell membranes and to the nucleus. A cells capability to respond to stimuli by several highly complex and dynamic signaling networks provides the basis for rapid responses and is fundamental for the cellular collaborations required in a multicellular organism. Having received diverse stimuli, being positioned at various stages of the cell cycle or, for the case of cancer, containing altered genetic background, each cell in a population is slightly different from its neighbor. However, bulk analyses of interactions will only reveal an average, but not the true variation within a population. Thus studies of interacting endogenous biomolecules in situ are essential to acquire a comprehensive view of cellular functions and communication. In situ proximity ligation assay (in situ PLA) was developed to investigate individual endogenous protein-protein interactions in fixed cells and tissues and was later applied for detection for PTMs. Progression of signals in a pathway can branch out in different directions and induce expression of different target genes. Hence simultaneous measurement of protein activity and gene expression provides a tool to determine the balance and progression of these signaling events. To obtain this in situ PLA was combined with padlock probes, providing an assay that can interrogate both PTMs and mRNA expression at a single cell level. Thereby different nodes of the signaling pathway as well as drug effects on different types of molecules could be investigated simultaneously. In addition to regulation of gene expression, protein-DNA interactions present a mechanism to manage accessibility of the genomic DNA in an inheritable manner, providing the basis for lineage commitment, via e.g. histone PTMs. To enable analyses of protein-DNA interactions in situ we developed a method that utilizes the proximity dependence of PLA and the sequence selectivity of padlock probes. This thesis presents new methods providing researchers with a set of tools to address cellular functions and communication in complex microenvironments, to improve disease diagnostics and to contribute to hopefully finding cures.
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Chang, Yuan-Pin. "Novel probes of angular momentum polarization." Thesis, University of Oxford, 2010. http://ora.ox.ac.uk/objects/uuid:d3880edf-436a-415e-8a74-6b1c0fd26e65.
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New dynamical applications of quantum beat spectroscopy (QBS) to molecular dynamics are employed to probe the angular momentum polarization effects in photodissociation and molecular collisions. The magnitude and the dynamical behaviour of angular momentum alignment and orientation, two types of polarization, can be measured via QBS technique on a shot-by-shot basis. The first part of this thesis describes the experimental studies of collisional angular momentum depolarization for the electronically excited state radicals in the presence of the collider partners. Depolarization accompanies both inelastic collisions, giving rise to rotational energy transfer (RET), and elastic collisions. Experimental results also have a fairly good agreement with the results of quasi-classical trajectory scattering calculations. Chapter 1 provides the brief theories about the application of the QBS technique and collisional depolarization. Chapter 2 describes the method and instrumentation employed in the experiments of this work. In Chapter 3, the QBS technique is used to measure the total elastic plus elastic depolarization rate constants under thermal conditions for NO(A,v=0) in the presence of He, Ar, N2, and O2. In the case of NO(A) with Ar, and particularly with He, collisional depolarization is significantly smaller than RET, reflecting the weak long-range forces in these systems. In the case of NO(A)+N2/O2, collisional depolarization and RET are comparable, reflecting the relatively strong long-range forces in these systems. In Chapter 4, the QBS technique is used to measure the elastic and inelastic depolarization and total RET rate constants for OH(A,v=0) under thermal conditions in the presence of He and Ar, as well as the total depolarization rate constants under superthermal conditions. In the case of OH(A)+He, elastic depolarization is sensitive to the N rotational state, and inelastic depolarization is strongly dependent on the collision energy. In the case of OH(A)+Ar, elastic depolarization is insensitive to N, and inelastic depolarization is less sensitive to the collision energy, reflecting that the relatively strong long-range force in OH(A)+Ar system. The second part of this thesis describes the experimental studies of photodissociation under thermal conditions. Chapter 5 provides a brief introduction about several polarization parameter formalisms used for photodissociation, and the incorporation of the QBS technique to measure these polarization parameters. In this thesis, most polarization parameters of the molecular photofragments are measured using the LIF method, and the QBS technique is used as a complementary tool to probe these polarization parameters. In Chapter 6, rotational orientation in the OH(X,v=0) photofragments from H2O2 photodissociation using circularly polarized light at 193 nm is observed. Although H2O2 can be excited to both the A and B electronic states by 193 nm, the observed orientation is only related to the A state dynamics. A proposed mechanism about the coupling between a polarized photon and the H2O2 parent rotation is simulated, and the good agreement between the experimental and simulation results further confirms the validity of this mechanism. In Chapter 7, rotational orientation in the NO(X,v) photofragments from NO2 photodissociation using circularly polarized light at 306 nm (v=0,1,2) and at 355 nm (v=0,1) is observed. Two possible mechanisms, the parent molecular rotation and the coherent effect between multiple electronic states, are discussed. NOCl is photodissociated using circularly polarized light at 306 nm, and NO(X,v) rotational distributions (v=0,1) and rotational orientation (v=0) are measured. For the case of NOCl, the generation of orientation is attributed to the coherent effect.
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Isaksson, Magnus. "Extracting Genomic Variations using Selector Technology." Doctoral thesis, Uppsala universitet, Institutionen för genetik och patologi, 2010. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-121429.
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This thesis describes the development and use of a new class of molecular tools called Selector probes, and its potential for investigations of genetic variation. The Selector technology provides multiplex amplification of targeted DNA sequences with a high specificity, and an enrichment factor in the same order of magnitude as PCR. A common feature in this thesis work is to focus the analysis on DNA regions of interest. For example, this technique can be implemented in analysing candidate regions found by whole genome studies that need validation (global to local analysis), and applications requiring detection of rare alleles (common to rare allele), important in for example cancer samples. An assay is presented that allows for fast and simple quantification of relative copy-number variations. The method was proven to be able to detect aneuploidy in chromosome 13, 18, 21 and X, with a resolution enough to distinguish between 4 and 5 copies. The method was successfully applied to solve a biological question regarding a copy-number variation, that explains the Ridge phenotype typical for the dog bread Rhodesian Ridgebacks. The Selector strategy was able to detect and map a tandem duplication with a size of 133 kb, which was characterized with base-pair resolution. A readout platform that facilitates simultaneous digital quantitative analysis of a large numbers of biomolecules is further introduced. The work involves arraying amplified product from successful selection and decoding each molecule by hybridization of fluorophore labeled oligonucleotides. Finally, a genome partitioning method which is applied upstream of next generation sequencing platforms is presented. It is shown that the method provides successful enrichment with 98 % coverage and 94 % specificity and high enrichment uniformity. The technique was applied for mutation analysis of 26 cancer-related genes in tumor cell-lines and tissue.
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Pan, Tianluo. "Scanning probe microscopy of poly-atomic molecules." Thesis, University of Birmingham, 2013. http://etheses.bham.ac.uk//id/eprint/4001/.
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This thesis presents studies on the adsorption of chlorobenzene using STS, non-local desorption of chlorobenzene and the atomic manipulation of the PCB molecule using STM. The atomic manipulation of the mucin molecule on HOPG surfaces under different conditions has also been investigated. Chlorobenzene adsorbate on the Si(111)-(7×7) surface has been investigated using STS. The missing rest atom state at -0.8 V confirmed the rest atom involvement in the bonding geometry. Two adsorbate states located at -1.3 V and +1 to +2 V have been identified. The effect of the surface step and the temperature on the non-local chlorobenzene desorption process has been investigated. Different reactions generated by STM of the PCB molecule on the Si(111)-(7×7) surface have been studied. While molecular desorption is maximized by electron injection into the chemisorbed molecular ring at low voltage, injection into the physisorbed molecular ring at high voltage favours the reconfiguration of the bonding. The mucin molecule has been studied by AFM and STM. An unraveling manipulation has been achieved over a folded mucin polymer on the bare HOPG surface. Enhanced mucin-substrate binding has also been achieved in the liquid state on the size-selected Au55 cluster-decorated HOPG surface.
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Schaefer, Giannina Ines. "Small-molecule probes to explore cancer." Thesis, Harvard University, 2014. http://dissertations.umi.com/gsas.harvard:11361.
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Small molecules play important roles in therapeutics and drug discovery. Significant progress has been made by the chemical biology community to discover small-molecule probes to explore biological processes and to treat disease. This thesis describes both the discovery of novel probes for the Hedgehog (Hh) pathway and the application of small molecules in identifying cancer dependencies.Chemistry and Chemical Biology
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Mezger, Anja. "Padlock Probe-Based Assays for Molecular Diagnostics." Doctoral thesis, Stockholms universitet, Institutionen för biokemi och biofysik, 2015. http://urn.kb.se/resolve?urn=urn:nbn:se:su:diva-116214.
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Treatment success often depends on the availability of accurate and reliable diagnostic assays to guide clinical practitioners in their treatment choices. An optimal test must excel in specificity and sensitivity, and depending on the application area time, low-cost and simplicity are equally important. For instance, time is essential in infectious diagnostics but this is less important in non-invasive prenatal testing (NIPT). In NIPT, specificity and sensitivity are the most important parameters. In this thesis I describe the development of four different methods, all based on padlock probes and rolling circle amplification, intended for molecular diagnostics. Application areas range from infectious disease diagnostics to NIPT and oncology. The methods described have in common that they overcome certain limitations of currently available assays. This thesis includes two new assays targeting infectious agents: one assay specifically detecting a highly variable double stranded RNA virus and the second assay demonstrating a new format of antibiotic susceptibility testing, which is rapid and generally applicable to different pathogens. Furthermore, I describe the development of a method that uses methylation markers to enrich fetal DNA, accurately quantify chromosome ratios and thus, detecting trisomy 21 and 18. The fourth method described in this thesis uses gap-fill ligation of padlock probes to detect diagnostic relevant point mutations with high specificity in situ. The assays presented have the potential, after automation and successful validation and verification studies, to be implemented into clinical practice. Furthermore, these assays demonstrate the wide applicability of padlock probes which, due to their properties in regard to specificity and multiplexity, are useful tools for nucleic acid detection in vitro as well as in situ.At the time of the doctoral defense, the following papers were unpublished and had a status as follows: Paper 3: Manuscript. Paper 4: Manuscript.
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Hanyu, Yuki. "Chemical scanning probe lithography and molecular construction." Thesis, University of Oxford, 2010. http://ora.ox.ac.uk/objects/uuid:409308ed-4806-44fc-87c3-5c1fe8971f79.
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The initiation and high resolution control of surface confined chemical reactions would be both beneficial for nanofabrication and fundamentally interesting. In this work, spatially controlled scanning probe directed organometallic coupling, patterned functional protein immobilisation and highly localised reversible redox reactions on SAMs were investigated. Catalytically active palladium nanoparticles were mounted on a scanning probe and an appropriate reagent SAM was scanned in a reagent solution. This instigated a spatially resolved organometallic coupling reaction between the solution and SAM-phase reagents. Within this catalytic nanolithography a spatial resolution of ~10nm is possible, equating to zeptomole-scale reaction. The methodology was applied to reactions such as Sonogashira coupling and local oligo(phenylene vinylene) synthesis. By altering the experimental protocols, relating probe scan velocity to reaction yield and characterising the nanopattern, a PVP matrix model describing a proposed mechanism of catalytic nanolithography, was presented. Though ultimately limited by probe deactivation, calculations indicated that activity per immobilised nanoparticle is very high in this configuration. For biopatterning, surface nanopatterns defined by carboxylic functionality were generated from methyl-terminated SAMs by local anodic oxidation (LAO) initiated by a conductive AFM probe. By employing suitable linker compounds, avidin and Stefin-A quadruple Mutant (SQM) receptive peptide aptamers were patterned at sub-100nm resolution. The multiplexed sensing capability of an SQM array was demonstrated by reacting generated patterns with single or a mixture of multiple antibodies. The reversible redox conversion and switching of reactivity of hydroquinone-terminated SAMs was electrochemically demonstrated prior to an application in redox nanolithography. In this methodology, spatially controlled probe-induced in situ "writing" and "erasing" based on reversible redox conversion were conducted on hydroquinone terminated SAM. In combination with dip-pen nanolithography, a novel method of redox electro-pen nanolithography was designed and the method’s application for lithography was examined.
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Yang, J.-J. "Chemiluminescent probes for biological molecules." Thesis, Swansea University, 1994. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.636704.
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This work describes the synthesis of new chemiluminescent ester compounds and their applications in immunoassay. The new compounds are 2,6-dibromo-4-(2-succinimidyl-oxycarbonylethyl)phenyl 10-methylacridinium-9-carboxylate trifluoromethanesulfonate (II), 2,6-dimethyl-4-(2-succinimidyloxycarbonylethyl)phenyl 10-methylacridinium-9-carboxylate trifluoromethanesulfonate (III), 2-(2-succinimidyloxycarbonylethyl)phenyl 10-methylacridinium-9-carboxylate trifluoromethanesulfonate (IV), 4,6-dibromo-2-(2-succinimidyloxycarbonylethyl)phenyl 10-methylacridinium-9-carboxylate trifluoromethane-sulfonate (V), 4,6-dimethyl-2-(2-succinimidyloxycarbonylethyl)phenyl 10-methyl-acridinium-9-carboxylate trifluoromethanesulfonate (VI) and 4-bromo-6-methyl-2-(2-succinimidyloxycarbonylethyl)phenyl 10-methylacridinium-9-carboxylate trifluoromethane-sulfonate (VII). All these compounds contain an acridinium ester unit, which provides the chemiluminescent moiety, a phenolate unit as a leaving group and a succinimidyl ester unit as a means of linking to biological molecules. The thesis is divided into two parts. The introduction gives a broad background and understanding of chemiluminescent biological probes. Initially the process of light emission is explained in brief. This is important because it is light emission from a chemical reaction that is chemiluminescence. This is followed by a description of the major chemiluminescence reagents, especially acridinium ester species as examples, and of how these can be used as labels in chemiluminescence immunoassay. The second part describes the synthesis of compounds (II), (III),(IV), (V), (VI), and (VII), together with som basic studies of theirchemiluminescent properties and attachment to Biblogical materials.
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Yuan, Wenjue. "Sas4 N terminal as a potential binding probe for tubulin-GDP." University of Toledo / OhioLINK, 2014. http://rave.ohiolink.edu/etdc/view?acc_num=toledo1399559850.
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Callaway, Martin James. "Thin films of flexible chain molecules." Thesis, University of Southampton, 1995. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.307080.
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Jirlén, Johan. "Nanolithography with molecules using advanced scanning probe microscopy methods." Thesis, Luleå tekniska universitet, Institutionen för teknikvetenskap och matematik, 2018. http://urn.kb.se/resolve?urn=urn:nbn:se:ltu:diva-68667.
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The possibilities of novel catalytic scanning probe lithography (cSPL) on starch using α-amylase was investigated. For this thin homogeneous layers of starch with good coverage were prepared by spin coating a starch solution on a silicon base. Amylase immobilized to an atomic force microscopy (AFM) cantilever tip were prepared and dragged along a spin coated starch surface. This after verifying the enzyme immobilization method using (3-Aminopropyl)triethoxysilane (APTES) on a silicon surface. In addition an unmodified cantilever tip were dipped in amylase solution and were dragged along a starch surface to investigate possibilities of dip-pen nanolithography (DPN). The preliminary experiments with AFM based enzymatic lithography were promising but non-conclusive. There are still many parameters not fully explored such as water availability, activity and reach of the amylase, speed of the enzymatic process and difference in structure between the starch and the shorter saccharides that are left after the hydrolysis
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Waibel, Michael. "Design and Synthesis of Molecules to Probe Peptidase Activity." Lyon, École normale supérieure (sciences), 2008. http://www.theses.fr/2008ENSL0503.
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Une première partie décrit le développement d'inhibiteurs de la protéase VIH-1, qui possèdent une structure hydrazine urée. Nous avons développé une voie de synthèse efficace et convergente pour accéder à des composés énantiopurs à partir de deux "building blocks" : l'un est un dérivé d'acides aminés, l'autre peut être facilement obtenu à partir d'amines secondaires. Les composés ont ensuite été testés avec la protéase VIH-1 dans un test basé sur la technologie FRET. Dans une seconde partie, nous avons développé une sonde fluorogène pour la détection d'activités enzymatiques. Dans cette molécule, le fluorophore 2-(2'-hydroxyphenyl)-4(3h)-quinazolinone (HPQ) est couplé par un epaceur auto-effondrable avec une unité dipeptidique qui peut être clivée par une enzyme. Nous avons pu démontrer que le site de clivage dipeptidique est coupé par la leucyl aminopeptidase, ce qui conduit à un auto-effondrement rapide de l'epaceur, résultant dans la génération d'un signal fluorescentThe first part of this Ph. D thesis describes the development of several HIV-1 peptidase inhibitors having a hydrazino-urea core. We have developed an efficient, convergent synthetic route to enantiopure compounds generated from two independent building blocks, one derived from amino acids, the other one from easily accessible hydrazines. All compounds were tested with HIV-1 peptidase in a FRET based enzyme assay. In a second part, we have developed a fluorogenic probe for the detection of peptidolyic activity. In this molecule, the fluorophore 2-(2'-hydroxyphenyl)-4(3h)-quinazolinone (HPQ) is coupled via a self-immolative spacer to an amide function that can be cleaved by an enzyme. We could demonstrate that the amide group is cleaved by commercial leucyl aminopeptidase which leads to rapid fragmentation of the spacer unit resulting in the generation of an intensly fluorescent signal
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Jung, Christophe, Jens Michaelis, Nadia Ruthardt, and Christoph Bräuchle. "Exploring diffusional behaviour in nanostructured systems with single molecule probes: Exploring diffusional behaviour in nanostructured systems withsingle molecule probes." Diffusion fundamentals 11 (2009) 68, S. 1-18, 2009. https://ul.qucosa.de/id/qucosa%3A14034.
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Brayshaw, Debra Jane. "Scanning probe microscopy studies of glycoconjugate molecular interactions." Thesis, University of Bristol, 2004. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.409424.
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Horton, Spencer Lourdes. "Photoionizaion as a Probe of Ultrafast Molecular Dynamics." Thesis, State University of New York at Stony Brook, 2018. http://pqdtopen.proquest.com/#viewpdf?dispub=10932704.
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Ionization can serve as a universal probe of excited state dynamics in molecules, such as internal conversion, dissociation, and isomerization. These processes are of fundamental importance to a wide array of dynamics in biology, chemistry and physics. In this thesis the topic of how to best construct a “molecular movie” of these photoinduced exited state molecular dynamics is addressed. Directly measuring a molecular structure or wave function amplitude as a function of time in order to construct a “molecular movie” is arguably impossible. Rather, the most insight is typically gained by comparing experiment with theoretical calculations of observables in order to verify the calculations, and then generating the “molecular movie” from calculations. Thus, an important criterion in evaluating different measurement approaches is how easily they can be compared with theoretical calculations of the measured observable.
Arguments are presented for why time-resolved ionization spectroscopy with a weak-field ionization probe is ideally suited for this goal. For the work conducted in this thesis, an ultrafast weak-field ionization pump-probe time-resolved ionization spectrometer is constructed utilizing UV (260 nm) and Vacuum-UV (156 nm) light to measure neutral excited state dynamics. Time-resolved VUV-pump UV-probe measurements were conducted to study of the highly excited states of pyrrole, where rapid internal conversion to the ground state appears to be the dominate relaxation channel. Time-resolved UV-pump and VUV-probe measurements in internal conversion of 1,3-cyclohexadiene are also performed. The measurements reveal a substantial ionization of the “hot” ground state following internal conversion despite the fact that our probe photon energy is below the ionization potential of the molecule. With the aid of electronic structure calculations, the results are interpreted in terms of vibrationally assisted below threshold ionization, where vibrational energy is converted to electronic energy. A comparison of time-resolved ionization spectroscopy is done using weak and strong field ionization as probes of these dynamics. It is found that though the two probes capture the same general dynamics only the weak-field ionization probe can be quantitatively compared to dynamics calculations. Lastly, weak-field ionization time-resolved photoelectron spectroscopy experiments are conducted on halogenated methanes. The high degree of agreement between the experiment and calculation enables us to construct “molecular movies” of the dynamics.
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Hecht, Bert. "Nanoscopic interactions probed by single molecules." Zürich : Laboratorium für Physikalische Chemie, Eidgenössische Technische Hochschule Zürich, 2002. http://e-collection.ethbib.ethz.ch/show?type=habil&nr=3.
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Abdur, Rashid Mohammad. "Theoretical interpretation of scanning probe images of molecules on surfaces." Thesis, University of Nottingham, 2017. http://eprints.nottingham.ac.uk/41928/.
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Scanning tunnelling microscopy (STM) and atomic force microscopy (AFM) can produce images of molecules with extremely high resolution. However, Claims that dynamic force microscopy has the capability to resolve intermolecular bonds in real space continue to be vigorously debated. Several studies have now shown that tip flexibility, especially at very close tip-sample separations, is responsible for the striking intra- and intermolecular resolution observed with various scanning probe microscopy techniques. The apparent intermolecular features can be observed with dynamic force microscopy even when no bonding interaction is present, suggesting that such features are in fact an artefact and cannot be interpreted as a real-space image of an intermolecular bond. We have studied the interaction between fullerene (C60) molecules using a sum of pairwise Lennard-Jones (12-6) potentials, and investigated how flexibility in the tip can produce a bond like feature between the molecules in a C60 island where there is no chemical bond present except the weak van der Waals force. We also investigate how the potential between the molecules is dependent on their relative orientations. For a given configuration of the tip and the sample molecules, our results allow us to predict the form of the intermolecular potential that would be observed using non contact atomic force microscopy (NC-AFM). Our study on the Si(111)-(7x7) reconstructed surface using the same model provides a better understating on the origin of ‘sub-atomic’ contrast observed in experiment suggesting that the contrast can arise from a flexible tip exploring an asymmetric potential created due to the positioning of the surrounding surface atoms. We have also simulated NC-AFM images of 2D bi-isonicotinic acid lattice using the same model. The geometry of the lattice have been optimized using DFT before simulating AFM images. Simulation results are in a good agreement with the experiment. The theoretical work is accompanied by a variety of experimental results obtained by the group of Prof Philip Moriarty at the University of Nottingham.
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Lakin, Andrew J. "Theoretical interpretation of scanning probe microscopy images involving organic molecules." Thesis, University of Nottingham, 2014. http://eprints.nottingham.ac.uk/14087/.
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Scanning probe microscopy allows the investigation and manipulation of matter at the atomic and molecular level, and is crucial in the development of new and novel techniques within nanoscience. However, to understand the information obtained from the various forms of scanning probe microscopy, a thorough theoretical understanding is necessary. Often this theoretical background is provided through density functional theory, which, while incredibly powerful, has limitations with regards to the size and complexity of the systems in which it can investigate. Thus, for more complicated systems, alternative techniques are desirable to be used both independently and alongside density functional theory. In this work, theoretical techniques are constructed that allow the information obtained from both scanning tunnelling microscopy and atomic force microscopy to be investigated for a variety of systems. These techniques are all based around Huckel molecular orbital theory or extended Huckel molecular orbital theory, and use a simple linear combination of atomic orbital basis, that allows rapid analysis of various systems. The main focus of the work is the scanning probe microscopy of the C60 fullerene molecule. Theoretical scanning tunnelling microscopy images are constructed for the cases where C60 is adsorbed on both the substrate and the scanning probe in the form of a functionalised tip, as well as when a tip-adsorbed molecule interacts with a sample-adsorbed molecule. The atomic force microscopy images of surface adsorbed C60 are considered, with the main focus centred on the repulsive interaction observed due to the Pauli exclusion principle. The structure of the scanning probe, and the effect this has on this imaging is examined, as well as considering the atomic force microscopy images obtained when two C60s interact. Molecules other than C60 are also considered, with the techniques developed used to interpret and understand the atomic force microscopy images obtained when a pentacene and a PTCDA molecule interact with a carbon monoxide functionalised tip. The theoretical work is accompanied throughout by a variety of experimental work, both from previously published work, and from unpublished work obtained by the University of Nottingham nanoscience group. Much focus is given to the interaction between C60 and the Si(111)-(7x7) reconstruction, both in the sense of a functionalised tip interacting with the surface, and with the interactions present where a C60 is adsorbed onto a surface. In doing so, previously postulated bonding sites for C60 on this surface have been verified.
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Chakraborty, Sourav. "Molecular Probes for Biologically Important Molecules: A Study of Thiourea, Hydroxyl radical, Peroxynitrite and Hypochlorous acid." ScholarWorks@UNO, 2010. http://scholarworks.uno.edu/td/1132.
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Numerous chemical species are important to the health of biological systems. Some species can be beneficial at low doses and harmful at high doses. Other species are highly reactive and trigger serious cell damage. Improved methods to detect the presence and activity of such species are needed. In this work, several biologically important species were studied using appropriate analytical techniques. Fluoride is an important species in human physiology. It strengthens teeth and gives protection against dental caries. However, elevated concentrations of fluoride in the body can lead to health problems such as dental and skeletal fluorosis. Reported fluoride sensors used fluorescence quenching methods in determining fluoride concentration. Our study explored synthesis and characterization of 1,8-bis(phenylthioureido) naphthalene (compound 1) as a fluoride sensing molecule. Compound 1 showed a remarkable 40 fold enhancement in fluorescence with 5 eq of fluoride addition. Compound 1 also showed possibility of visual colorimetric sensing with fluoride. Free radical mediated oxidations of biomolecules are responsible for different pathological conditions in the human body. Superoxide is generated in cells and tissues during oxidative burst. Moderately reactive superoxide is converted to peroxyl, alkoxyl and hydroxyl radicals by various enzymatic, chemical, and biochemical processes. Hydroxyl radical imparts rapid, non specific oxidative damage to biomolecules such as proteins and lipids. Superoxide also reacts with nitric oxide in cells to yield peroxynitrite, which is highly reactive and damages biomolecules. Both hydroxyl radical and peroxynitrite readily react with amino acids containing aromatic side chains. Low density lipoprotein (LDL) carries cholesterol in the human body. Elevated concentration of LDL is a potential risk factor for atherosclerosis. Previous research drew a strong correlation between oxidized low density lipoprotein (ox-LDL) and plaque formation in the arterial wall. More importantly, oxidative damage causes structural changes to the LDL protein (apo B-100) which might facilitate the uptake of LDL by macrophages. In this study LDL was exposed to various concentrations of hydroxyl radical peroxynitrite and hypochlorite. Thereafter oxidized amino acid residues in apo B-100 were mapped by LC-MS/MS methods. We found widely distributed oxidative modifications in the apo B-100 amino acid sequence.
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Nathubhai, Amit. "Molecular probes for mammalian chitinases." Thesis, University of Bath, 2010. https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.518107.
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Chitin is a glycopolymer consisting of +-(1, 4)-linked N-acetyl-D-glucosamine residues that occurs widely in nature and is a constituent of many organisms that are pathogenic to humans, including insects, fungi, and parasitic nematodes. As these organisms depend on the ability to break down chitin at key points of their life-cycle, inhibitors of the enzymes termed chitinases that catalyse the hydrolysis of chitin, are of considerable interest as potential drugs and insecticides. Although chitin is absent from mammalian physiology, two human chitinases along with several chitin-binding proteins (chi-lectins) have been associated with the onset or transmission of several major human diseases such as asthma, Legionnaire’s disease and osteoarthritis. Therefore, selective inhibitors of chitinases are now of considerable interest as new drug leads and biochemical probes. Until recently, few broad spectrum chitinase inhibitors had been identified. The natural cyclopentapeptide, argifin, has been shown to be a potent inhibitor of several bacterial-type family 18 chitinases including Aspergillus fumigatus chitinase B1 (AfChiB1). With the aid of high resolution X-ray structures we have designed and prepared linear fragments of the natural product cyclopentapeptide argifin using a combination of SPPS and solution phase synthesis. This has allowed us to determine that the Nmethyl guanylurea motif serves as a starting point for the generation of novel, drug-like, peptidomimetic inhibitors family 18 chitinases. We have also demonstrated that the cis configuration about the Arg(MC)-N-MePhe peptide bond is essential to retain any significant biological activity. This dipeptide motif is also found in another naturally occurring cyclopentapeptide, banyasin A, extracted from the cyanobacteruim Nostoc sp. Banyasin A also contains a rare +-amino acid, 3-amino-2-methyl-5E-octenoic acid (Amoa), in which the stereochemistry at the C3 and C5 of Amoa has not been resolved. The diastereoselective synthesis of Amoa for the preparation of banyasin A has also been established using chiral oxazolidinone-based aldol chemistry, which has allowed us to successfully prepare a single diastereoisomer of the natural product cyclopentapeptide incorporating this +-amino acid. New methodology for the preparation of argifin has also been developed to reduce the propensity towards the formation of undesired side products and to prepare the natural product on a larger scale.
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Ajayi, Olubode Olumuyiwa. "Probe atomisation in electrothermal atomic absorption spectrometry." Thesis, University of Strathclyde, 1988. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.314558.
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Xing, Li. "Non-enveloped virus infection probed with host cellular molecules : a structural study /." Stockholm, 2002. http://diss.kib.ki.se/2002/91-7349-289-2.
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McKee, Erik. "Femtosecond Filament Interaction as a Probe for Molecular Alignment." Master's thesis, University of Central Florida, 2013. http://digital.library.ucf.edu/cdm/ref/collection/ETD/id/5991.
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Femtosecond laser filamentation is a highly nonlinear propagation mode. When a laser pulse propagates with a peak power exceeding a critical value Pcr (5 GW at 800 nm in air), the Kerr effect tends to collapse the beam until the intensity is high enough to ionize the medium, giving rise to plasma defocusing. A dynamic competition between these two effects takes place leaving a thin and weakly ionized plasma channel in the trail of the pulse.
When an ultrafast laser pulse interacts with molecules, it will align them, spinning them about their axis of polarization. As the quantum rotational wave packet relaxes, the molecules will experience periodic field-free alignment. Recent work has demonstrated the effect of molecular alignment on laser filamentation of ultra-short pulses. Revival of the molecular alignment can modify filamentation parameters as it can locally modify the refractive index and the ionization rate. In this thesis, we demonstrate with simulations and experiments that these changes in the filament parameters (collapse distance and filament plasma length) can be used to probe molecular alignment in CO2.M.S.
Masters
Optics and Photonics
Optics and Photonics
Optics
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Hutchinson, William Edward. "Molecular sensing using immobilized IR-active carbonylmetal probe groups." Thesis, Nottingham Trent University, 2001. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.369254.
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Chen, Lei. "Molecular Tools for Biomarker Detection." Doctoral thesis, Uppsala universitet, Molekylära verktyg, 2017. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-331745.
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The advance of biological research promotes the emerging of new methods and solutions to answer the biological questions. This thesis describes several new molecular tools and their applications for the detection of genomic and proteomic information with extremely high sensitivity and specificity or simplify such detection procedures without compromising the performance. In paper I, we described a general method namely super RCA, for highly specific counting of single DNA molecules. Individual products of a range of molecular detection reactions are magnified to Giga-Dalton levels that are easily detected for counting one by one, using methods such as low-magnification microscopy, flow cytometry, or using a mobile phone camera. The sRCA-flow cytometry readout presents extremely high counting precision and the assay’s coefficient of variation can be as low as 0.5%. sRCA-flow cytometry readout can be applied to detect the tumor mutations down to 1/100,000 in the circulating tumor cell-free DNA. In paper II, we applied the super RCA method into the in situ sequencing protocol to enhance the amplified mRNA detection tags for better signal-to-noise ratios. The sRCA products co-localize with primary RCA products generated from the gene specific padlock probes and remain as a single individual object in during the sequencing step. The enhanced sRCA products is 100% brighter than regular RCA products and the detection efficiency at least doubled with preserved specificity using sRCA compared to standard RCA. In paper III, we described a highly specific and efficient molecular switch mechanism namely RCA reporter. The switch will initiate the rolling circle amplification only in the presence of correct target sequences. The RCA reporter mechanism can be applied to recognize single stranded DNA sequences, mRNA sequences and sequences embedded in the RCA products. In paper IV, we established the solid phase Proximity Ligation Assay against the SOX10 protein using poly clonal antibodies. Using this assay, we found elevated SOX10 in serum at high frequency among vitiligo and melanoma patients. While the healthy donors below the threshold.
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Bendiksen, Bård A., Espen H. Blokkdal, and Eddy W. Hansen. "Unconsolidated material characteristics obtained by PFGNMR using (two) different probe molecules." Universitätsbibliothek Leipzig, 2015. http://nbn-resolving.de/urn:nbn:de:bsz:15-qucosa-183710.
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Bendiksen, Bård A., Espen H. Blokkdal, and Eddy W. Hansen. "Unconsolidated material characteristics obtained by PFGNMR using (two) different probe molecules." Diffusion fundamentals 20 (2013) 83, S. 1-2, 2013. https://ul.qucosa.de/id/qucosa%3A13670.
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Shebanits, Oleg. "Pre-biotic molecules and dynamics in the ionosphere of Titan : a space weather station perspective." Licentiate thesis, Uppsala universitet, Institutet för rymdfysik, Uppsalaavdelningen, 2015. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-248118.
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Saturn’s largest moon Titan (2575 km radius) is the second largest in the Solar system. Titan is the only known moon with a fully developed nitrogen-rich atmosphere with ionosphere extending to ~2000 km altitude, hosting complex organic chemistry. One of the main scientific interests of Titan’s atmosphere and ionosphere is the striking similarity to current theories of those of Earth ~3.5 billion years ago. The Cassini spacecraft has been in orbit around Saturn since 2004 and carries a wide range of instruments for investigating Titan’s ionosphere, among them the Langmuir probe, a “space weather station”, manufactured and operated by the Swedish Institute of Space Physics, Uppsala. This thesis reviews the first half of the PhD project on the production of pre-biotic molecules in the atmosphere of Titan and early Earth, focusing on the ion densities and dynamics in Titan’s ionosphere derived from the in-situ measurements by the Cassini Langmuir probe. One of the main results is the detection of significant, up to ~2300 cm-3, charge densities of heavy (up to ~13000 amu) negative ions in Titan’s ionosphere below 1400 km altitude. On the nightside of the ionosphere at altitudes below 1200 km, the heavy negative ion charge densities are comparable to the positive ion densities and are in fact the main negative charge carrier, making this region of the ionosphere exhibit properties of dusty plasma. The overall trend is the exponential increasing of the negative ion charge densities towards lower altitudes. Another important result is the detection of ion drifts that between 880-1100 km altitudes in Titan’s ionosphere translate to neutral winds of 0.5-5.5 km/s. Ion drifts define three regions by altitude, the top layer (above ~1600 km altitude) where the ions are frozen into the background magnetic field, the dynamo region (1100 – 1600 km altitudes) where the ions are drifting in partly opposing directions due to ion-neutral collisions in the presence of the magnetic and electric fields and the bottom layer (below 1100 km altitude) of the ionosphere, where the ions are coupled to neutrals by collisions.