83 research outputs found

    Deep Evolutionary Generative Molecular Modeling for RNA Aptamer Drug Design

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    Deep Aptamer Evolutionary Model (DAPTEV Model). Typical drug development processes are costly, time consuming and often manual with regard to research. Aptamers are short, single-stranded oligonucleotides (RNA/DNA) that bind to, and inhibit, target proteins and other types of molecules similar to antibodies. Compared with small-molecule drugs, these aptamers can bind to their targets with high affinity (binding strength) and specificity (designed to uniquely interact with the target only). The typical development process for aptamers utilizes a manual process known as Systematic Evolution of Ligands by Exponential Enrichment (SELEX), which is costly, slow, and often produces mild results. The focus of this research is to create a deep learning approach for the generating and evolving of aptamer sequences to support aptamer-based drug development. These sequences must be unique, contain at least some level of structural complexity, and have a high level of affinity and specificity for the intended target. Moreover, after training, the deep learning system, known as a Variational Autoencoder, must possess the ability to be queried for new sequences without the need for further training. Currently, this research is applied to the SARS-CoV-2 (Covid-19) spike protein’s receptor-binding domain (RBD). However, careful consideration has been placed in the intentional design of a general solution for future viral applications. Each individual run took five and a half days to complete. Over the course of two months, three runs were performed for three different models. After some sequence, score, and statistical comparisons, it was observed that the deep learning model was able to produce structurally complex aptamers with strong binding affinities and specificities to the target Covid-19 RBD. Furthermore, due to the nature of VAEs, this model is indeed able to be queried for new aptamers of similar quality based on previous training. Results suggest that VAE-based deep learning methods are capable of optimizing aptamer-target binding affinities and specificities (multi-objective learning), and are a strong tool to aid in aptamer-based drug development

    A model for polymer membranes

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    Separation processes are widely used throughout the chemical and pharmaceutical industries. Polymer membranes have the potential to significantly improve both energy usage and the costs of separation processes by reducing reliance on fractional distillation. For this to occur methods to control the porosity of the polymer membranes must be identified. The P84 molecule is a relatively complex co-polymer with numerous strongly interacting rigid groups, with a persistence length of over 1.1 nm, and the region in which filtration pores form in the membrane is typically 50–80nm thick, whilst the pores of interest within the membrane are typically less than 0.5 nm in size. P84 membranes are used commercially to separate molecules from organic solvents, in a process called organic solvent nanofiltration. Recent experiments with membranes produced from the P84 polyimide molecule found that altering the solvent used in the initial stage of manufacture radically altered the size of the sub-nanometre pores in the filtration region of the membrane. This effect was not expected, and could not be explained by the available models for polymer membrane formation. I present here a model as well as key results developed during my investigation of the formation of P84 polymer membranes. The model uses a mixture of fully atomistic molecular dynamics simulations of a single P84 molecule in solvent and coarse grained Monte Carlo simulations containing hundreds of complete polymer molecules. It demonstrates that the experimentally observed changes in pore sizes in P84 membranes can be explained by the differing interaction energies between the solvents and the polymers. I further present a new method for coarse graining aromatic polymers in molecular dynamics simulations which has been shown to permit the time step to be increased from 1 fs to 5 fs whilst maintaining all-atom accuracy.Open Acces

    Whole-transciptome analysis of [psi+] budding yeast via cDNA microarrays

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    Introduction: Prions of yeast present a novel analytical challenge in terms of both initial characterization and in vitro manipulation as models for human disease research. Presently, few robust analysis strategies have been successfully implemented which enable the efficient study of prion behavior in vivo. This study sought to evaluate the utilization of conventional dual-channel cDNA microarrays for the surveillance of transcriptomic regulation patterns by the [PSI+] yeast prion relative to an identical prion deficient yeast variant, [psi-]. Methods: A data analysis and normalization workflow strategy was developed and applied to cDNA array images, yielded quality-regulated expression ratios for a subset of genes exhibiting statistical congruence across multiple experimental repetitions and nested hybridization events. The significant gene list was analyzed using classical analytical approaches including several clustering-based methods and singular value decomposition. To add biological meaning to the differential expression data in hand, functional annotation using the Gene Ontology as well as several pathway-mapping approaches was conducted. Finally, the expression patterns observed were queried against all publicly curated microarray data performed using S. cerevisiae in order to discover similar expression behavior across a vast array of experimental conditions. Results: These data collectively implicate a low-level of overall genomic regulation as a result of the [PSI+] state, where the maximum statistically significant degree of differential expression was less than ±1 Log2(FC) in all cases. Notwithstanding, the [PSI+] differential expression was localized to several specific classes of structural elements and cellular functions, implying under homeostatic conditions significant up or down regulation is likely unnecessary but possible in those specific systems if environmental conditions warranted. As a result of these findings additional work pertaining to this system should include controlled insult to both yeast variants of differing environmental properties to promote a potential [PSI+] regulatory response coupled with co-surveillance of these conditions using transcriptomic and proteomic analysis methodologies

    Logic and Automata

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    Mathematical logic and automata theory are two scientific disciplines with a fundamentally close relationship. The authors of Logic and Automata take the occasion of the sixtieth birthday of Wolfgang Thomas to present a tour d'horizon of automata theory and logic. The twenty papers in this volume cover many different facets of logic and automata theory, emphasizing the connections to other disciplines such as games, algorithms, and semigroup theory, as well as discussing current challenges in the field

    Essential Speech and Language Technology for Dutch: Results by the STEVIN-programme

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    Computational Linguistics; Germanic Languages; Artificial Intelligence (incl. Robotics); Computing Methodologie

    Conflict-driven learning in AI planning state-space search

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    Many combinatorial computation problems in computer science can be cast as a reachability problem in an implicitly described, potentially huge, graph: the state space. State-space search is a versatile and widespread method to solve such reachability problems, but it requires some form of guidance to prevent exploring that combinatorial space exhaustively. Conflict-driven learning is an indispensable search ingredient for solving constraint satisfaction problems (most prominently, Boolean satisfiability). It guides search towards solutions by identifying conflicts during the search, i.e., search branches not leading to any solution, learning from them knowledge to avoid similar conflicts in the remainder of the search. This thesis adapts the conflict-driven learning methodology to more general classes of reachability problems. Specifically, our work is placed in AI planning. We consider goal-reachability objectives in classical planning and in planning under uncertainty. The canonical form of "conflicts" in this context are dead-end states, i.e., states from which the desired goal property cannot be reached. We pioneer methods for learning sound and generalizable dead-end knowledge from conflicts encountered during forward state-space search. This embraces the following core contributions: When acting under uncertainty, the presence of dead-end states may make it impossible to satisfy the goal property with absolute certainty. The natural planning objective then is MaxProb, maximizing the probability of reaching the goal. However, algorithms for MaxProb probabilistic planning are severely underexplored. We close this gap by developing a large design space of probabilistic state-space search methods, contributing new search algorithms, admissible state-space reduction techniques, and goal-probability bounds suitable for heuristic state-space search. We systematically explore this design space through an extensive empirical evaluation. The key to our conflict-driven learning algorithm adaptation are unsolvability detectors, i.e., goal-reachability overapproximations. We design three complementary families of such unsolvability detectors, building upon known techniques: critical-path heuristics, linear-programming-based heuristics, and dead-end traps. We develop search methods to identify conflicts in deterministic and probabilistic state spaces, and we develop suitable refinement methods for the different unsolvability detectors so to recognize these states. Arranged in a depth-first search, our techniques approach the elegance of conflict-driven learning in constraint satisfaction, featuring the ability to learn to refute search subtrees, and intelligent backjumping to the root cause of a conflict. We provide a comprehensive experimental evaluation, demonstrating that the proposed techniques yield state-of-the-art performance for finding plans for solvable classical planning tasks, proving classical planning tasks unsolvable, and solving MaxProb in probabilistic planning, on benchmarks where dead-end states abound.Viele kombinatorisch komplexe Berechnungsprobleme in der Informatik lassen sich als Erreichbarkeitsprobleme in einem implizit dargestellten, potenziell riesigen, Graphen - dem Zustandsraum - verstehen. Die Zustandsraumsuche ist eine weit verbreitete Methode, um solche Erreichbarkeitsprobleme zu lösen. Die Effizienz dieser Methode hängt aber maßgeblich von der Verwendung strikter Suchkontrollmechanismen ab. Das konfliktgesteuerte Lernen ist eine essenzielle Suchkomponente für das Lösen von Constraint-Satisfaction-Problemen (wie dem Erfüllbarkeitsproblem der Aussagenlogik), welches von Konflikten, also Fehlern in der Suche, neue Kontrollregeln lernt, die ähnliche Konflikte zukünftig vermeiden. In dieser Arbeit erweitern wir die zugrundeliegende Methodik auf Zielerreichbarkeitsfragen, wie sie im klassischen und probabilistischen Planen, einem Teilbereich der Künstlichen Intelligenz, auftauchen. Die kanonische Form von „Konflikten“ in diesem Kontext sind sog. Sackgassen, Zustände, von denen aus die Zielbedingung nicht erreicht werden kann. Wir präsentieren Methoden, die es ermöglichen, während der Zustandsraumsuche von solchen Konflikten korrektes und verallgemeinerbares Wissen über Sackgassen zu erlernen. Unsere Arbeit umfasst folgende Beiträge: Wenn der Effekt des Handelns mit Unsicherheiten behaftet ist, dann kann die Existenz von Sackgassen dazu führen, dass die Zielbedingung nicht unter allen Umständen erfüllt werden kann. Die naheliegendste Planungsbedingung in diesem Fall ist MaxProb, das Maximieren der Wahrscheinlichkeit, dass die Zielbedingung erreicht wird. Planungsalgorithmen für MaxProb sind jedoch wenig erforscht. Um diese Lücke zu schließen, erstellen wir einen umfangreichen Bausatz für Suchmethoden in probabilistischen Zustandsräumen, und entwickeln dabei neue Suchalgorithmen, Zustandsraumreduktionsmethoden, und Abschätzungen der Zielerreichbarkeitswahrscheinlichkeit, wie sie für heuristische Suchalgorithmen gebraucht werden. Wir explorieren den resultierenden Gestaltungsraum systematisch in einer breit angelegten empirischen Studie. Die Grundlage unserer Adaption des konfliktgesteuerten Lernens bilden Unerreichbarkeitsdetektoren. Wir konzipieren drei Familien solcher Detektoren basierend auf bereits bekannten Techniken: Kritische-Pfad Heuristiken, Heuristiken basierend auf linearer Optimierung, und Sackgassen-Fallen. Wir entwickeln Suchmethoden, um Konflikte in deterministischen und probabilistischen Zustandsräumen zu erkennen, sowie Methoden, um die verschiedenen Unerreichbarkeitsdetektoren basierend auf den erkannten Konflikten zu verfeinern. Instanziiert als Tiefensuche weisen unsere Techniken ähnliche Eigenschaften auf wie das konfliktgesteuerte Lernen für Constraint-Satisfaction-Problemen. Wir evaluieren die entwickelten Methoden empirisch, und zeigen dabei, dass das konfliktgesteuerte Lernen unter gewissen Voraussetzungen zu signifikanten Suchreduktionen beim Finden von Plänen in lösbaren klassischen Planungsproblemen, Beweisen der Unlösbarkeit von klassischen Planungsproblemen, und Lösen von MaxProb im probabilistischen Planen, führen kann

    Simulated penetration testing and mitigation analysis

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    Da Unternehmensnetzwerke und Internetdienste stetig komplexer werden, wird es immer schwieriger, installierte Programme, Schwachstellen und Sicherheitsprotokolle zu überblicken. Die Idee hinter simuliertem Penetrationstesten ist es, Informationen über ein Netzwerk in ein formales Modell zu transferiern und darin einen Angreifer zu simulieren. Diesem Modell fügen wir einen Verteidiger hinzu, der mittels eigener Aktionen versucht, die Fähigkeiten des Angreifers zu minimieren. Dieses zwei-Spieler Handlungsplanungsproblem nennen wir Stackelberg planning. Ziel ist es, Administratoren, Penetrationstestern und der Führungsebene dabei zu helfen, die Schwachstellen großer Netzwerke zu identifizieren und kosteneffiziente Gegenmaßnahmen vorzuschlagen. Wir schaffen in dieser Dissertation erstens die formalen und algorithmischen Grundlagen von Stackelberg planning. Indem wir dabei auf klassischen Planungsproblemen aufbauen, können wir von gut erforschten Heuristiken und anderen Techniken zur Analysebeschleunigung, z.B. symbolischer Suche, profitieren. Zweitens entwerfen wir einen Formalismus für Privilegien-Eskalation und demonstrieren die Anwendbarkeit unserer Simulation auf lokale Computernetzwerke. Drittens wenden wir unsere Simulation auf internetweite Szenarien an und untersuchen die Robustheit sowohl der E-Mail-Infrastruktur als auch von Webseiten. Viertens ermöglichen wir mittels webbasierter Benutzeroberflächen den leichten Zugang zu unseren Tools und Analyseergebnissen.As corporate networks and Internet services are becoming increasingly more complex, it is hard to keep an overview over all deployed software, their potential vulnerabilities, and all existing security protocols. Simulated penetration testing was proposed to extend regular penetration testing by transferring gathered information about a network into a formal model and simulate an attacker in this model. Having a formal model of a network enables us to add a defender trying to mitigate the capabilities of the attacker with their own actions. We name this two-player planning task Stackelberg planning. The goal behind this is to help administrators, penetration testing consultants, and the management level at finding weak spots of large computer infrastructure and suggesting cost-effective mitigations to lower the security risk. In this thesis, we first lay the formal and algorithmic foundations for Stackelberg planning tasks. By building it in a classical planning framework, we can benefit from well-studied heuristics, pruning techniques, and other approaches to speed up the search, for example symbolic search. Second, we design a theory for privilege escalation and demonstrate the applicability of our framework to local computer networks. Third, we apply our framework to Internet-wide scenarios by investigating the robustness of both the email infrastructure and the web. Fourth, we make our findings and our toolchain easily accessible via web-based user interfaces
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