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Senast publicerade
- Reverse Transcriptase Characterization and Engineering for Genome Editing(2026) Emy, SaetreAbstract Templated editing, consisting of a Cas9 enzyme coupled to a reverse transcriptase (RT) directed by a programmable guide RNA to install edits in the genome, offers unprecedented potential for treating genetic diseases. Yet, translation to clinical applications is hindered by unpredictable editing efficiency and limited understanding of how RT properties influence outcomes. This thesis systematically characterized a panel of established and novel RTs, including engineered Moloney Murine Leukemia Virus (MMLV) derivatives, compact bacterial RTs, and AstraZeneca-proprietary candidates, through complementary cellular and in vitro assays to establish rational engineering principles. A HiBiT reporter system enabled high-throughput quantification of templated editing (TE) efficiency in cellulo, while biochemical assays were used to measure polymerization activity, DNA/RNA binding affinity, thermostability, and aggregation propensity. Results suggested that successful templated editing requires optimization of three critical properties: thermostability, protein solubility, and DNA/RNA substrate affinity. Two iterative rational engineering cycles based on this hypothesis highlighted a synergistic relationship between the three properties. Engineered variants that combine solubility, stability and substrate affinity enhancements achieved up to 2.4 times higher editing efficiency compared to the established state-of-the-art benchmarks. By systematically defining the biochemical and biophysical property thresholds required for TE efficiency, this work establishes an evidence-based design framework that transform RT development from empirical screening toward rational, predictive engineering, diminishing optimization timelines and accelerating therapeutic development.
- Evolution Strategies as an Alternative to Reinforcement Learning in De Novo Molecular Generation - Evaluating Distribution Based Gaussian Evolution Strategies in REINVENT vs. Policy Based Reinforcement Learning on the Practical Molecular Optimization Benchmark(2026) Eklöv, MalvaDe novo molecular generation examines how computational methods can propose novel drug candidates by scoring generated molecules against desired properties and updating generation toward higher scoring regions. One approach trains a SMILES based language model and fine tunes it toward such regions. Fine tuning is commonly performed with policy gradient reinforcement learning (RL), as in AstraZenecas highly optimized REINVENT platform. An alternative is evolutionary strategies (ES), where a population of models is created and their parameters are updated to bias generation toward higher scores. This thesis investigates how distribution based ES compares with RL when implemented in REINVENT and evaluated on the Practical Molecular Optimization benchmark. OpenAI-ES shows near competitive performance on scoring and diversity metrics, whereas variance estimating Natural ES methods perform poorly. Variations of fixed variance ES are explored, and a novel sampling technique that biases generation toward high diversity shows promising performance across multiple metrics.
- Data-Driven Requirement Development - From Field Data to Reliability Requirements: Identifying and Analyzing High-Performing Automotive ECUs(2026) Wang, YiminThis thesis investigates a data-driven methodology for reliability-oriented requirement development in automotive electronics. Traditional automotive reliability engineering is primarily failure-focused, relying on warranty analysis and reactive investigation of defective components. However, such approaches provide limited understanding of why certain Electronic Control Units (ECUs) consistently demonstrate strong field reliability performance. The research initially aimed to analyze relationships between ECU operational conditions and field reliability behavior through classical data-driven analysis. However, the required centralized operational-condition dataset was not available within the industrial data environment. Consequently, the study evolved toward a practical industrial screening methodology based on available enterprise engineering and field-quality data resources. The proposed framework integrates multiple industrial datasets, including the KDP Engineering Database (KDP), Quality Follow-Up (QFU) warranty repair records, the Early Warning System (EWS), and procurement-related production volume data. By combining field repair occurrence with market exposure normalization, ECU populations with exceptionally low repair occurrence relative to deployment volume were identified. Selected ECUs subsequently underwent hardware-oriented engineering investigation, including open-lid assessment, Printed Circuit Board (PCB)-level visual inspection, and review of available Design Verification (DV) and Product Validation (PV) documentation. The investigation focused on identifying recurring robustness-related engineering characteristics rather than performing direct failure analysis. Observed features included reinforced PCB mechanical support structures, controlled PCB cleanliness, environmental protection strategies, and evidence of robustness-oriented validation practices. The work demonstrates how multiple industrial engineering and field-quality data sources can be systematically combined to support evidence-based reliability investigation and practical reliability requirement development in automotive electronics.
- Existence of Static Solutions to the Vlasov-Poisson and Einstein-Vlasov Systems as Fixed Points of a Mass-Preserving Algorithm(2026) Lehmann, LudvigThis thesis develops a new method for proving the existence of static, spherically symmetric solutions to the Einstein–Vlasov system by reformulating a masspreserving algorithm as a fixed-point problem. Building on earlier work for the Vlasov–Poisson system, we first extend an existing fixed-point existence proof from isotropic to anisotropic solutions. We then establish the corresponding result for the Einstein–Vlasov system, using a simple isotropic ansatz.