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  • image/svg+xml art designer at PLoS, modified by Wikipedia users Nina, Beao, JakobVoss, and AnonMoos Open Access logo, converted into svg, designed by PLoS. This version with transparent background. http://commons.wikimedia.org/wiki/File:Open_Access_logo_PLoS_white.svg art designer at PLoS, modified by Wikipedia users Nina, Beao, JakobVoss, and AnonMoos http://www.plos.org/
    Authors: Rogers, Joel;

    Natural evolution has yielded small molecules and macromolecules with a diverse array of activities, many of which have been harnessed by human society to advance industry and medicine. However, evolution is primarily selective for survival of the organism and/or gene rather than any particular activity directly, and is largely constrained by its cellular environment — interference or negative interactions (such as precipitation or cytotoxicity) between the cell and effector (the RNA or protein product) will generally act as a counter-selective pressure for that effector. Evolution also lacks foresight. In fact, evolution’s main advantage over human efforts to develop novel drugs or catalysts seems to be the sheer number of molecules that it has been able to sample over the past ~3.5 billion years — as well as the fact that the cell is a relatively robust and efficient core platform on which to build. Ultrahigh-throughput screening offers researchers a powerful tool to begin sampling larger regions of sequence space, and thus partially addresses one of evolution’s main advantages. This approach has particularly grown in promise and scale as DNA sequencing has become faster, cheaper and more accurate in recent years, greatly facilitating identification of macromolecular — and in some cases, small molecule — library members. Combining the ability to screen large libraries with a clear concept of our desired activity can provide useful insights into the relationship between molecular-scale structure and function, in addition to facilitating the development of novel, ‘artificial’ candidates that evolution may not have explored or been exposed to before. This latter feature is more significant than it may first appear, as many of the challenges faced by modern humanity are likely to be the product of survivorship or observation bias — i.e. those problems that natural evolution has already solved or could feasibly solve are less likely to present challenges to us in the first place. Nevertheless, the vast majority of existing approaches are still constrained by cellular expression. Additionally, low-throughput assays for a given activity are often difficult to adapt for ultrahigh-throughput approaches. To help address these challenges, we have developed a platform which is capable of displaying generic DNA and protein on biologically inert and microfluidic-compatible polyacrylamide microbeads. We envision this as an ultrahigh-throughput-compatible, robust, abiotic tool for maintaining the genotype-effector (“phenotype”) linkage over several experimental steps (e.g. PCR, in vitro expression, and the assay itself), as well as a generally applicable module for protein purification, solid-phase (DNA) synthesis, etc. Our platform’s compatibility with in vitro expression may allow exploration of novel sequence space which is poorly accessible in cellulo, and we hope that this will provide novel opportunities for naïve phenotypic screening and drug lead compound discovery. In this thesis, I will first present my work in characterising and enhancing protein immobilisation on these beads using a fully covalent, suicide substrate-based linkage module we developed (polyacrylamide-benzylguanine-SNAP-SpyCatcher-SpyTag; Chapter 1). I find that the beads are highly permeable to proteins, and that protein-display capacity is largely determined by methacrylatebenzylguanine’s input concentration, copolymerisation efficiency and accessibility, but can reach at least 100 μM in practice. Next, we combine this capture method with other protein modules to create two purification and multivalent (up to 30X) assembly workflows for SpyTagged proteins (Chapter 2). I explore the impact of construct valency on the potency of apoptosis induction for two TRAIL-receptor agonists, observing that potency is strongly dependent on agonist valency and therefore likely also on microdomain formation (‘lipid rafting’) for TRAIL-receptor. We use multimerisation to achieve a ~5 pM EC50 for a multivalent assembly of a nanobody, compared to an EC50 of at least 115 nM of the same nanobody in its monovalent form (a more than 2.3×10⁴-fold potency improvement). We simultaneously present clickable modules to control valency which are ‘plug-and-play’ with our protein capture module from Chapter 1, and which can be readily expressed and employed by others. In Chapter 3, I demonstrate and refine an ultrahigh-throughput-compatible phenotypic screen for bacteriolysis. I show that this assay is sensitive to antimicrobial peptide-induced lysis under treatment conditions which could theoretically be achieved using microfluidics and bead protein capacity levels as demonstrated in Chapter 1, although the low potency of antimicrobial peptides makes this practically non-trivial. I therefore begin the process of optimising the practical steps necessary to effectively deliver such a large on-bead payload, beginning with our protease-based solubilisation step and in vitro transcription-translation in Chapter 4.

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  • image/svg+xml art designer at PLoS, modified by Wikipedia users Nina, Beao, JakobVoss, and AnonMoos Open Access logo, converted into svg, designed by PLoS. This version with transparent background. http://commons.wikimedia.org/wiki/File:Open_Access_logo_PLoS_white.svg art designer at PLoS, modified by Wikipedia users Nina, Beao, JakobVoss, and AnonMoos http://www.plos.org/
    Authors: Robert C. North;
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    Authors: Jonathon Pan;
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  • Authors: Flavel, Ambika;
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  • image/svg+xml art designer at PLoS, modified by Wikipedia users Nina, Beao, JakobVoss, and AnonMoos Open Access logo, converted into svg, designed by PLoS. This version with transparent background. http://commons.wikimedia.org/wiki/File:Open_Access_logo_PLoS_white.svg art designer at PLoS, modified by Wikipedia users Nina, Beao, JakobVoss, and AnonMoos http://www.plos.org/
    Authors: Wenchi Peter Pan;
    image/svg+xml art designer at PLoS, modified by Wikipedia users Nina, Beao, JakobVoss, and AnonMoos Open Access logo, converted into svg, designed by PLoS. This version with transparent background. http://commons.wikimedia.org/wiki/File:Open_Access_logo_PLoS_white.svg art designer at PLoS, modified by Wikipedia users Nina, Beao, JakobVoss, and AnonMoos http://www.plos.org/ https://dr.lib.iasta...arrow_drop_down
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  • Authors: Prötsch, Corinna;

    Im Rahmen der vorliegenden Diplomarbeit konnten insgesamt neun neue Verbindungen (1a-c, 2a-c, 3a-c) synthetisiert werden. Bei den Zielstrukturen des Typs 3 handelt es sich um Ring-A-modifizierte Derivate des Alkaloids Luotonin A, welches aufgrund seiner ausgeprägten Topoisomerase-I-Hemmwirkung von pharmazeutischem Interesse ist. Die nunmehr zugänglich gemachten 9,12-, 10,12- und 11,12-disubstituierten Abkömmlinge der genannten Leitstruktur sollen vorrangig zur Gewinnung neuer Informationen über die Struktur-Wirkungsbeziehungen in dieser Klasse antitumor-aktiver Verbindungen dienen. Zur Herstellung der Zwischenstufen 1a-c kam die Weinreb-Amidierung zum Einsatz. Aus dem literaturbekannten Ethyl-4-oxo-3,4-dihydrochinazolin-2-carboxylat und dem entsprechenden 2,3-, 2,4- bzw. 2,5-dimethylierten Anilin wurde unter Aktivierung des Anilin-Stickstoffes mithilfe von Trimethylaluminium das jeweilige N-(Dimethylphenyl)- 4-oxo-3,4-dihydrochinazolin-2-carboxamid (1) in sehr guter Ausbeute hergestellt. Im nächsten Schritt wurden die Anilide des Typs 1 mit Propargylbromid/Kaliumcarbonat in Dimethylformamid selektiv an N-3 alkyliert. Im letzten Schritt erfolgte die Zyklisierung der so erhaltenen N-Propargyl- Verbindungen 2a-c zu den Zielverbindungen 3a-c in einer intramolekularen [4+2]- Cycloadditionsreaktion schon bei Raumtemperatur unter Einwirkung des Hendrickson-Reagens. Letzteres wird dabei in situ aus Triphenylphosphinoxid und Trifluormethansulfonsäureanhydrid hergestellt. In the present thesis nine new compounds (1a-c, 2a-c, 3a-c) were synthesized. The target structures of the type 3 are ring-A-modified derivatives of the alkaloid Luotonin A, which is due to its strong topoisomerase I inhibitory activity of pharmaceutical interest. The now available made 9,12, 10,12 and 11,12-disubstituted derivatives of the chemical lead should serve primarily to acquire new information about the structure-activity relationships in this class of antitumor-active compounds. For the preparation of the intermediates 1a-c the Weinreb amidation was used. Ethyl 4-oxo-3,4-dihydroquinazoline-2-carboxylate and the corresponding 2,3, 2,4 and 2,5-dimethylated aniline were used through activation of the aniline nitrogen using the trimethylaluminum to synthesis N-(dimethylphenyl) - 4-oxo-3,4-dihydroquinazolin-2-carboxamide in very good yield. In the next step, the anilides of type 1 were selectively alkylated at N-3 with propargyl bromide / potassium carbonate in dimethylformamide. In the last step, the cyclization of the thus obtained N-propargyl compounds 2a-c was carried out to the target compounds 3a-c in an intramolecular [4 +2] - cycloaddition reaction at room temperature under the action of Hendrickson reagent. The latter is thereby produced in situ from triphenylphosphine and triflic anhydride.

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  • image/svg+xml art designer at PLoS, modified by Wikipedia users Nina, Beao, JakobVoss, and AnonMoos Open Access logo, converted into svg, designed by PLoS. This version with transparent background. http://commons.wikimedia.org/wiki/File:Open_Access_logo_PLoS_white.svg art designer at PLoS, modified by Wikipedia users Nina, Beao, JakobVoss, and AnonMoos http://www.plos.org/
    Authors: Osanlou, Kevin;

    This thesis explores the benefits machine learning algorithms can bring to online planning and scheduling for autonomous vehicles in off-road situations. Mainly, we focus on typical problems of interest which include computing itineraries that meet certain objectives, as well as computing scheduling strategies to execute synchronized maneuvers with other vehicles. We present a range of learning-based heuristics to assist different itinerary planners. We show that these heuristics allow a significant increase in performance for optimal planners. Furthermore, in the case of approximate planning, we show that not only does the running time decrease, the quality of the itinerary found also becomes almost always better. Finally, in order to synthesize strategies to execute synchronized maneuvers, we propose a novel type of scheduling controllability and a learning-assisted algorithm. The proposed framework achieves significant improvement on known benchmarks in this controllability type over the performance of state-of-the-art works in a related controllability type. Moreover, it is able to find strategies on complex scheduling problems for which previous works fail to do so. Comment: PhD thesis

    image/svg+xml art designer at PLoS, modified by Wikipedia users Nina, Beao, JakobVoss, and AnonMoos Open Access logo, converted into svg, designed by PLoS. This version with transparent background. http://commons.wikimedia.org/wiki/File:Open_Access_logo_PLoS_white.svg art designer at PLoS, modified by Wikipedia users Nina, Beao, JakobVoss, and AnonMoos http://www.plos.org/ arXiv.org e-Print Ar...arrow_drop_down
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    arXiv.org e-Print Archive
    Other literature type . Preprint . 2021
    https://doi.org/10.48550/arxiv...
    Article . 2021
    License: CC BY NC ND
    Data sources: Datacite
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    Thesis . 2021
    Data sources: Datacite
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      Other literature type . Preprint . 2021
      https://doi.org/10.48550/arxiv...
      Article . 2021
      License: CC BY NC ND
      Data sources: Datacite
      ResearchGate Data
      Thesis . 2021
      Data sources: Datacite
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  • Authors: Hemetsberger, Susanne Ingeborg;

    Jedes Jahr werden Tonnen von synthetischen Substanzen in der Landwirtschaft eingesetzt, um Insekten, Unkraut oder andere Schädlinge, wie Pilze oder Viren, fernzuhalten oder zu töten. Diese Produkte können jedoch auch die Gesundheit und die Umwelt schädigen. Ätherische Öle stellen hier eine gute Alternative dar, um jene schädlichen Substanzen zu ersetzen oder zu ergänzen. Besonders profitieren können dabei allerdings weniger die Industrieländer als die sogenannten „Schwellenländer“, in denen sich die Bauern die weniger toxischen Stoffe, die bei uns bereits eingesetzt werden, nicht leisten können. Ätherische Öle können sowohl als Pestizide als auch als Repellent, Unkrautvertilgungsmittel und als Mittel, um Pilze und Viren zu beseitigen, verwendet werden. Sie spielen auch eine wichtige Rolle bei der Verlängerung der Haltbarkeit von gelagerten Produkten. Every year tons of synthetic products are used in agriculture in order to keep away or kill harmful insects, weed or other pests like fungi or viruses. These substances are harmful towards human health and environment. Essential oils bear a great potential to replace synthetic products or to complement them. Even though they might not be that important in industrialized countries they can be very useful in less industrialized countries where farmers can't afford even less toxic syntheticals, as e. g. in Europe. Essential oils can be used as pesticide, insect repellent, weed management substance, or as inhibitor of fungi and viruses. They also play an important role for stored products.

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    Authors: Ali, Athar;
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26 Research products
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    Authors: Rogers, Joel;

    Natural evolution has yielded small molecules and macromolecules with a diverse array of activities, many of which have been harnessed by human society to advance industry and medicine. However, evolution is primarily selective for survival of the organism and/or gene rather than any particular activity directly, and is largely constrained by its cellular environment — interference or negative interactions (such as precipitation or cytotoxicity) between the cell and effector (the RNA or protein product) will generally act as a counter-selective pressure for that effector. Evolution also lacks foresight. In fact, evolution’s main advantage over human efforts to develop novel drugs or catalysts seems to be the sheer number of molecules that it has been able to sample over the past ~3.5 billion years — as well as the fact that the cell is a relatively robust and efficient core platform on which to build. Ultrahigh-throughput screening offers researchers a powerful tool to begin sampling larger regions of sequence space, and thus partially addresses one of evolution’s main advantages. This approach has particularly grown in promise and scale as DNA sequencing has become faster, cheaper and more accurate in recent years, greatly facilitating identification of macromolecular — and in some cases, small molecule — library members. Combining the ability to screen large libraries with a clear concept of our desired activity can provide useful insights into the relationship between molecular-scale structure and function, in addition to facilitating the development of novel, ‘artificial’ candidates that evolution may not have explored or been exposed to before. This latter feature is more significant than it may first appear, as many of the challenges faced by modern humanity are likely to be the product of survivorship or observation bias — i.e. those problems that natural evolution has already solved or could feasibly solve are less likely to present challenges to us in the first place. Nevertheless, the vast majority of existing approaches are still constrained by cellular expression. Additionally, low-throughput assays for a given activity are often difficult to adapt for ultrahigh-throughput approaches. To help address these challenges, we have developed a platform which is capable of displaying generic DNA and protein on biologically inert and microfluidic-compatible polyacrylamide microbeads. We envision this as an ultrahigh-throughput-compatible, robust, abiotic tool for maintaining the genotype-effector (“phenotype”) linkage over several experimental steps (e.g. PCR, in vitro expression, and the assay itself), as well as a generally applicable module for protein purification, solid-phase (DNA) synthesis, etc. Our platform’s compatibility with in vitro expression may allow exploration of novel sequence space which is poorly accessible in cellulo, and we hope that this will provide novel opportunities for naïve phenotypic screening and drug lead compound discovery. In this thesis, I will first present my work in characterising and enhancing protein immobilisation on these beads using a fully covalent, suicide substrate-based linkage module we developed (polyacrylamide-benzylguanine-SNAP-SpyCatcher-SpyTag; Chapter 1). I find that the beads are highly permeable to proteins, and that protein-display capacity is largely determined by methacrylatebenzylguanine’s input concentration, copolymerisation efficiency and accessibility, but can reach at least 100 μM in practice. Next, we combine this capture method with other protein modules to create two purification and multivalent (up to 30X) assembly workflows for SpyTagged proteins (Chapter 2). I explore the impact of construct valency on the potency of apoptosis induction for two TRAIL-receptor agonists, observing that potency is strongly dependent on agonist valency and therefore likely also on microdomain formation (‘lipid rafting’) for TRAIL-receptor. We use multimerisation to achieve a ~5 pM EC50 for a multivalent assembly of a nanobody, compared to an EC50 of at least 115 nM of the same nanobody in its monovalent form (a more than 2.3×10⁴-fold potency improvement). We simultaneously present clickable modules to control valency which are ‘plug-and-play’ with our protein capture module from Chapter 1, and which can be readily expressed and employed by others. In Chapter 3, I demonstrate and refine an ultrahigh-throughput-compatible phenotypic screen for bacteriolysis. I show that this assay is sensitive to antimicrobial peptide-induced lysis under treatment conditions which could theoretically be achieved using microfluidics and bead protein capacity levels as demonstrated in Chapter 1, although the low potency of antimicrobial peptides makes this practically non-trivial. I therefore begin the process of optimising the practical steps necessary to effectively deliver such a large on-bead payload, beginning with our protease-based solubilisation step and in vitro transcription-translation in Chapter 4.

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    Authors: Robert C. North;
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    Authors: Jonathon Pan;
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  • Authors: Flavel, Ambika;
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    Authors: Wenchi Peter Pan;
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