Biology subjects

Krüger, J.

Publications and source records attributed to Krüger, J..

5 recordsLinked to original sources

bioRxiv2025

A structured evaluation and benchmarking of Boolean logical modelling tools

Biomolecules form complex interaction systems at different biological levels. The dynamics behind the interactions of biomolecules result in cellular phenotypes and responses. Two typical biological interaction systems are signal transduction and gene regulatory networks. Boolean models characterise these systems components with binary state variables and their interactions with rules governing their influence on each other, without requiring kinetic and abundance information about these components. Tools are available to define, analyse, and manage these models, but there is a lack of an overview and evaluation of such tools quality and functionality. This work aims to facilitate the selection of software tools for Boolean modelling of signal transduction and gene regulatory networks by developing benchmark and evaluation criteria and applying them to the available tools. Twenty Boolean modelling tools were identified, which were assessed on their compliance to ten FAIR4RS (Findability, Accessibility, Interoperability, and Reusability for Research Software) aspects. Additionally, usability was assessed using a set of 25 developed sub-criteria. Furthermore, the functionalities were analysed, validated and the tools abilities to simulate and analyse Boolean models of different sizes were benchmarked. The evaluation demonstrated that, whilst the results produced by the 20 tools were completely consistent, their analytical functionalities and capabilities to simulate larger models varied widely. Size constraints for tools functionalities ranged between 25 and more than 10,000 nodes. Each tool only covered part of the available functionalities, and many exhibited deficiencies in FAIR4RS compliance and usability. Based on our analysis, we see great potential for researchers to improve the usability of their tools along the FAIR4RS aspects in the future, with average tools in our evaluation not yet addressing 40% of the aspects (20% for the best-performing one). The aim is to present a useful overview of usability and functionality of Boolean modelling tools and to show how they can be improved throughout the entire community. Author summaryOur study provides a set of criteria and a benchmarking toolkit for evaluating FAIR4RS and usability aspects as well as functionalities of Boolean modelling tools. We establish an overview of a wide range of Boolean modelling tools for signal transduction and gene regulatory network modelling, which is intended to make it easier for users to choose software according to their needs. This work empowers developers by offering crucial assets: a standardised evaluation criteria set for comparing their tools functionalities, usability, and FAIR4RS compliance throughout the community. Our models and benchmarking assets further enable developers to precisely determine and improve their softwares model size limitations.

systems biology↗

bioRxiv2025

Reduced harmonic complexity of brain parenchymal cardiovascular pulse waveforms in Alzheimer's disease

Alzheimers disease (AD) is characterized by specific neuropathologies, and is associated with arterial wall {beta}-amyloid accumulations, which lead to radiologically detectable amplitude increases and variable propagation speed of cardiovascular impulses in brain. In this study, we developed a fast frequency domain imaging method know as relative harmonic power of magnetic resonance encephalography (MREGRHP), aiming to investigate the configuration of the cardiovascular impulses independently of the mean magnetic resonance signal intensity and physiological impulse amplitude. In the initial analyses in healthy controls, we found that a wide 0.8 - 5Hz bandpass produced the most physiologically realistic cardiovascular waveforms. Whereas the data recorded in cerebrospinal fluid (CSF) from flip angle (FA) of 25{degrees} yielded up to 7-fold higher cardiac signal intensity as compared to FA of 5{degrees}, within the brain tissue recordings with FA of 5{degrees} were markedly more sensitive to cardiac waveform. We detected arterial impulses originating from major arteries and extending into the surrounding brain parenchyma, with simultaneous dampening of amplitude as a function of distance from source. Finally, we compared MREGRHP results in 34 AD patients (mean age: 60.7{+/-}4.7 years; 53% female) against 29 controls (mean age: 56.9{+/-}7.9 years; 66% female). We show that the harmonic power of cardiovascular brain pulses is significantly reduced in cortical frontoparietal areas of AD patients, indicating monotonous impulse patterns colocalizing with the previously reported areas of increased impulse propagation speed. In conclusion, the MREGRHP offers a fast Fourier transform (FFT)-based method to non-invasively quantify and locate human arterial blood vessel wall pathology.

neuroscience↗

bioRxiv2024

Leveraging zebrafish embryo phenotypic observations to advance data-driven analyses in toxicology

Zebrafish have emerged as a central model organism in toxicological research. Zebrafish embryos are exempt from certain animal testing regulations which facilitates their use in toxicological testing. Next to the zebrafish embryo acute toxicity test (ZFET) according to the OECD TG 236, fish embryos are used in mechanistic investigations, chemical screenings, in ecotoxicology, and drug development. However, inconsistencies in the applied test protocols and the monitored endpoints in addition to a lack of standardized data formats, impede comprehensive meta-analyses and cross-study comparisons. To address these challenges, we developed the Integrated Effect Database for Toxicological Observations (INTOB), a comprehensive data management tool that standardizes collection of metadata and phenotypic observations using a controlled vocabulary. By incorporating data from more than 600 experiments into the database and subsequent comprehensive data analyses, we demonstrate its utility in improving the comparability and interoperability of toxicity data. Our results show that the ZFET can detect toxicity spanning seven orders of magnitude at the scale of effect concentrations. We also highlight the potential of read-across analyses based on morphological fingerprints and their connection to chemical modes of action, provide information on control variability of the ZFET, and highlight the importance of time for mechanistic understanding in chemical exposure-effect assessments. We provide the full FAIR dataset as well as the analysis workflow and demonstrate how professional data management, as enabled with INTOB, marks a significant advancement by offering a comprehensive framework for the systematic use of zebrafish embryo toxicity data, thus paving the way for more reliable, data-driven chemical risk assessment. SynopsisThis article shows how a novel data management tool for zebrafish embryo toxicity data advances comparative chemical risk assessment by enhancing data and metadata standardization, comparability, and cross-study analyses.

pharmacology and toxicology↗

bioRxiv2023

Retigabine and gabapentin restore channel function and neuronal firing of an epilepsy-associated dominant-negative KCNQ5 variant

ObjectiveKCNQ5 encodes the voltage-gated potassium channel KV7.5, a member of the KV7 channel family, which conducts the M-current. This current was shown to be a potent regulator of neuronal excitability by mediating the medium and slow afterhyperpolarization. Recently, we have identified five loss-of-function variants in KCNQ5 in patients with genetic generalized epilepsy. Using the most severe dominant-negative variant p.(Arg359Cys) (R359C), we set out to investigate pharmacological therapeutic intervention by KV7 channel openers on channel function and neuronal firing. MethodsWhole-cell patch clamp recordings were conducted in human embryonic kidney cells to investigate the immediate effect of retigabine, gabapentin and intracellular application of zinc on the R359C variant in absence and presence of KV7.5-WT subunits. Transfected primary hippocampal cultures were used to examine the effect of R359C on neuronal firing and whether this effect could be reversed by drug application. ResultsRetigabine and gabapentin both increased R359C-derived K+ current density and M-current amplitudes in both homomeric and heteromeric mutant KV7.5 channels. Retigabine was most effective in restoring K+ currents. Ten {micro}M retigabine was sufficient to reach the level of WT currents without retigabine, whereas 100 {micro}M of gabapentin showed less than half of this effect and application of 50 {micro}M zinc only significantly increased M-current amplitude in heteromeric channels. Overexpression of KV7.5-WT potently inhibited neuronal firing by increasing the M-current, and medium afterhyperpolarization, whereas R359C overexpression had the opposite effect. All three aforementioned drugs reversed the effect of R359C reducing firing to nearly normal levels at high current injections. SignificanceOur study shows that a dominant-negative complete loss-of-function variant in KV7.5 leads to largely increased neuronal firing indicating a neuronal hyperexcitability. KV7 channel openers, such as retigabine or gabapentin, could be treatment options for otherwise pharmacoresistant epilepsy patients carrying loss-of-function variants in KCNQ5.

neuroscience↗

bioRxiv2021

Developing and deploying an integrated workshop curriculum teaching computational skills for reproducible research

Inspired by well-established material and pedagogy provided by The Carpentries (Wilson 2016), we developed a two-day workshop curriculum that teaches introductory R programming for managing, analyzing, plotting and reporting data using packages from the tidyverse (Wickham et al. 2019), the Unix shell, version control with git, and GitHub. While the official Software Carpentry curriculum is comprehensive, we found that it contains too much content for a two-day workshop. We also felt that the independent nature of the lessons left learners confused about how to integrate the newly acquired programming skills in their own work. Thus, we developed a new curriculum that aims to teach novices how to implement reproducible research principles in their own data analysis. The curriculum integrates live coding lessons with individual-level and group-based practice exercises, and also serves as a succinct resource that learners can reference both during and after the workshop. Moreover, it lowers the entry barrier for new instructors as they do not have to develop their own teaching materials or sift through extensive content. We developed this curriculum during a two-day sprint, successfully used it to host a two-day virtual workshop with almost 40 participants, and updated the material based on instructor and learner feedback. We hope that our new curriculum will prove useful to future instructors interested in teaching workshops with similar learning objectives.

scientific communication and education↗