EI-HPC - Enabling Infrastructure for HPC-Applications (DE/BMBF/13FH156IN6)
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In this thesis it is posed that the central object of preference discovery is a co-creative process in which the Other can be represented by a machine. It explores efficient methods to enhance introverted intuition using extraverted intuition's communication lines. Possible implementations of such processes are presented using novel algorithms that perform divergent search to feed the users' intuition with many examples of high quality solutions, allowing them to take influence interactively. The machine feeds and reflects upon human intuition, combining both what is possible and preferred. The machine model and the divergent optimization algorithms are the motor behind this co-creative process, in which machine and users co-create and interactively choose branches of an ad hoc hierarchical decomposition of the solution space.
The proposed co-creative process consists of several elements: a formal model for interactive co-creative processes, evolutionary divergent search, diversity and similarity, data-driven methods to discover diversity, limitations of artificial creative agents, matters of efficiency in behavioral and morphological modeling, visualization, a connection to prototype theory, and methods to allow users to influence artificial creative agents. This thesis helps putting the human back into the design loop in generative AI and optimization.
Mebendazole Mediates Proteasomal Degradation of GLI Transcription Factors in Acute Myeloid Leukemia
(2021)
The prognosis of elderly AML patients is still poor due to chemotherapy resistance. The Hedgehog (HH) pathway is important for leukemic transformation because of aberrant activation of GLI transcription factors. MBZ is a well-tolerated anthelmintic that exhibits strong antitumor effects. Herein, we show that MBZ induced strong, dose-dependent anti-leukemic effects on AML cells, including the sensitization of AML cells to chemotherapy with cytarabine. MBZ strongly reduced intracellular protein levels of GLI1/GLI2 transcription factors. Consequently, MBZ reduced the GLI promoter activity as observed in luciferase-based reporter assays in AML cell lines. Further analysis revealed that MBZ mediates its anti-leukemic effects by promoting the proteasomal degradation of GLI transcription factors via inhibition of HSP70/90 chaperone activity. Extensive molecular dynamics simulations were performed on the MBZ-HSP90 complex, showing a stable binding interaction at the ATP binding site. Importantly, two patients with refractory AML were treated with MBZ in an off-label setting and MBZ effectively reduced the GLI signaling activity in a modified plasma inhibitory assay, resulting in a decrease in peripheral blood blast counts in one patient. Our data prove that MBZ is an effective GLI inhibitor that should be evaluated in combination to conventional chemotherapy in the clinical setting.
Recent experimental evidence suggest that mebendazole, a popular antiparasitic drug, binds to heat shock protein 90 (Hsp90) and inhibit acute myeloid leukemia cell growth. In this study we use quantum mechanics (QM), molecular similarity and molecular dynamics (MD) calculations to predict possible binding poses of mebendazole to the adenosine triphosphate (ATP) binding site of Hsp90. Extensive conformational searches and minimization of the five tautomers of mebendazole using MP2/aug-cc-pVTZ theory level resulting in 152 minima being identified. Mebendazole-Hsp90 complex models were created using the QM optimized conformations and protein coordinates obtained from experimental crystal structures that were chosen through similarity calculations. Nine different poses were identified from a total of 600 ns of explicit solvent, all-atom MD simulations using two different force fields. All simulations support the hypothesis that mebendazole is able to bind to the ATP binding site of Hsp90.
Turbulent compressible flows are traditionally simulated using explicit time integrators applied to discretized versions of the Navier-Stokes equations. However, the associated Courant-Friedrichs-Lewy condition severely restricts the maximum time-step size. Exploiting the Lagrangian nature of the Boltzmann equation’s material derivative, we now introduce a feasible three-dimensional semi-Lagrangian lattice Boltzmann method (SLLBM), which circumvents this restriction. While many lattice Boltzmann methods for compressible flows were restricted to two dimensions due to the enormous number of discrete velocities in three dimensions, the SLLBM uses only 45 discrete velocities. Based on compressible Taylor-Green vortex simulations we show that the new method accurately captures shocks or shocklets as well as turbulence in 3D without utilizing additional filtering or stabilizing techniques other than the filtering introduced by the interpolation, even when the time-step sizes are up to two orders of magnitude larger compared to simulations in the literature. Our new method therefore enables researchers to study compressible turbulent flows by a fully explicit scheme, whose range of admissible time-step sizes is dictated by physics rather than spatial discretization.
Off-lattice Boltzmann methods increase the flexibility and applicability of lattice Boltzmann methods by decoupling the discretizations of time, space, and particle velocities. However, the velocity sets that are mostly used in off-lattice Boltzmann simulations were originally tailored to on-lattice Boltzmann methods. In this contribution, we show how the accuracy and efficiency of weakly and fully compressible semi-Lagrangian off-lattice Boltzmann simulations is increased by velocity sets derived from cubature rules, i.e. multivariate quadratures, which have not been produced by the Gauß-product rule. In particular, simulations of 2D shock-vortex interactions indicate that the cubature-derived degree-nine D2Q19 velocity set is capable to replace the Gauß-product rule-derived D2Q25. Likewise, the degree-five velocity sets D3Q13 and D3Q21, as well as a degree-seven D3V27 velocity set were successfully tested for 3D Taylor–Green vortex flows to challenge and surpass the quality of the customary D3Q27 velocity set. In compressible 3D Taylor–Green vortex flows with Mach numbers on-lattice simulations with velocity sets D3Q103 and D3V107 showed only limited stability, while the off-lattice degree-nine D3Q45 velocity set accurately reproduced the kinetic energy provided by literature.
Risk-based authentication (RBA) aims to strengthen password-based authentication rather than replacing it. RBA does this by monitoring and recording additional features during the login process. If feature values at login time differ significantly from those observed before, RBA requests an additional proof of identification. Although RBA is recommended in the NIST digital identity guidelines, it has so far been used almost exclusively by major online services. This is partly due to a lack of open knowledge and implementations that would allow any service provider to roll out RBA protection to its users.
To close this gap, we provide a first in-depth analysis of RBA characteristics in a practical deployment. We observed N=780 users with 247 unique features on a real-world online service for over 1.8 years. Based on our collected data set, we provide (i) a behavior analysis of two RBA implementations that were apparently used by major online services in the wild, (ii) a benchmark of the features to extract a subset that is most suitable for RBA use, (iii) a new feature that has not been used in RBA before, and (iv) factors which have a significant effect on RBA performance. Our results show that RBA needs to be carefully tailored to each online service, as even small configuration adjustments can greatly impact RBA's security and usability properties. We provide insights on the selection of features, their weightings, and the risk classification in order to benefit from RBA after a minimum number of login attempts.