Biology subjects

Schaller, S.

Publications and source records attributed to Schaller, S..

8 recordsLinked to original sources

bioRxiv2025

High-throughput PBK modelling for dermal exposure: a pragmatic approach to predict systemic pharmacokinetics

High-throughput physiologically based kinetic (HT-PBK) modelling provides a mechanistic framework for predicting systemic pharmacokinetics (PK) from in vitro and in silico data, supporting non-animal chemical safety assessment within Next generation risk assessment (NGRA). Here, we applied HT-PBK modelling to dermal exposure, a key route of human contact with chemicals. Using the skin permeation model of the Open Systems Pharmacology Suite, we simulated systemic PK profiles of 52 compounds based solely on physicochemical properties predicted by quantitative structure-activity relationship (QSAR) models and without any compound-specific in vitro measurements. We systematically compared different QSAR tools for lipophilicity, solubility, and other parameters to identify optimal model parameterisation strategies. Across all compounds, the best-performing HT-PBK strategy predicted 75% of Cmax and AUC values within a tenfold range of observed human plasma data extracted from published clinical studies. A systematic tendency toward overprediction of systemic PK was observed, likely due to missing study metadata and the default assumption of fully hydrated skin. Prediction errors were larger for dermal than for oral exposure, reflecting the greater complexity and variability of dermal absorption processes. Nevertheless, key exposure metrics were reproduced within acceptable limits. These results demonstrate the feasibility of fully in silico, non-animal HT-PBK modelling for dermal absorption and support its use as a pragmatic tool for exposure-driven safety assessment within NGRA frameworks.

pharmacology and toxicology↗

bioRxiv2025

Integration of In Vitro and In Silico Approaches Enables Prediction of Drug-Induced Liver Injury

Drug-induced liver injury (DILI) is a major cause of drug attrition and poses a significant threat to patient safety. However, current preclinical prediction methods, including heuristic screening rules, in vitro assays, machine learning models and animal testing, have serious limitations. Here, we demonstrate that combining in vitro toxicity data (cytotoxicity, mitochondrial toxicity, bile salt export pump (BSEP) inhibition) with pharmacokinetic information enables high DILI predictivity. In a retrospective analysis of 241 drugs, we show that the ratio of their in vivo maximum plasma concentration (Cmax) to their lowest in vitro toxicity strongly correlates with clinical DILI risks, with ROC AUC up to 96%. Then, we show that comparable predictivity (ROC AUC up to 91%) is achievable prospectively when Cmax values are predicted in silico by high-throughput physiologically based kinetic modelling. Dynamic simulations of bile acid perturbations further identify drugs potentially causing DILI specifically through BSEP inhibition, providing additional mechanistic insights. This integrative, mechanistic approach shows enhanced DILI predictivity and interpretability, offering an animal-free alternative for early drug development.

pharmacology and toxicology↗

bioRxiv2025

Microbial sedimentary DNA from a cultural landscape disentangles the impacts of humans and nature over the past 13.5 thousand years

Bacteria and archaea are currently under-characterised in palaeoecological studies, despite their ubiquity, high diversity and tight integration with the biotic and abiotic environment and human activity. The complexity of their assemblages, and the difficulties in separating living- from paleo-prokaryotes renders analyses challenging. Here we present an ancient prokaryote metagenomic time-series from a sediment core of Lake Constance, a large and deep perialpine lake from temperate Europe, spanning the last 13,500 years of natural and anthropogenic impact. We mapped DNA to reference genomes and estimated the DNA damage of taxa, which displayed a monotonic relationship with time. By constructing co-abundance networks we recognize major microbial assemblages, containing both ancient and living microbes, that show specific dynamics. Short-term and often low-abundance assemblages are linked to the Pleistocene-Holocene transition, floods and human activities. Noticeably, certain lineages harbouring microbes common in human-impacted environments expanded during the Middle Ages and Modern time. Some abundant taxa that were linked to various freshwater and soil environments persisted through millennia. By extricating various sources and trajectories of change, we demonstrate the power of prokaryotic sedimentary DNA in revealing long-term eco-evolutionary outcomes caused by both nature- and humans.

ecology↗

bioRxiv2025

Potential Systemic Availability Classification of Chemicals for Safety Assessment

The assessment of chemical safety is essential for protecting human health, yet current approaches have severe limitations. They are unable to address the rapidly growing number of substances requiring evaluation and further rely on animal testing, which the public expects to be phased out for ethical reasons. To address this, the European Partnership for Alternative Approaches to Animal Testing (EPAA) proposed the use of a novel framework for the classification of systemic toxicity based on new approach methodologies. One dimension of this framework is the grouping of substances into different classes of Potential Systemic Availability (PSA) concern (low, medium, high). But so far it remained conceptually and practically unclear how this classification can be achieved. Here, we outline the theoretical considerations for a health-protective definition of PSA concern classes and present a method for the quantitative evaluation of this property. Using high-throughput physiologically based kinetic modelling, we are able to classify the PSA concerns of 139 out of 150 EPAA NAM Designathon compounds. Further, we manually annotate these compounds to evaluate the plausibility of predicted classifications against expert judgement. Our results outline under which circumstances it is appropriate to prioritise or deprioritise chemicals due to their toxicokinetic properties. However, we find that most compounds cannot be assessed on their PSA alone and need to be considered medium PSA concern so that classification into any overall systemic toxicity concern class remains possible. Future integration of bioactivity data will be necessary to fully judge the utility of our method and of the entire framework.

pharmacology and toxicology↗

bioRxiv2024

Systematic Evaluation of High-Throughput PBK Modelling Strategies for the Prediction of Intravenous and Oral Pharmacokinetics in Humans

Physiologically based kinetic (PBK) modelling offers a mechanistic basis for predicting the pharmaco-/toxicokinetics of compounds and thereby provides critical information for integrating toxicity and exposure data to replace animal testing with in vitro or in silico methods. However, traditional PBK modelling depends on animal and human data, which limits its usefulness for Non-Animal Methods. To address this limitation, High-throughput PBK modelling aims to rely exclusively on in vitro and in silico data for model generation. Here, we evaluate a variety of in silico tools and different strategies to parameterise PBK models with input values from various sources in a high-throughput manner. We gather 2000+ publicly available human in vivo concentration-time profiles of 200+ compounds (IV and oral administration), as well as in silico, in vitro and in vivo determined compound-specific parameters required for the PBK modelling of these compounds. Then, we systematically evaluate all possible PBK model parametrisation strategies in PK-Sim and quantify their prediction accuracy against the collected in vivo concentration-time profiles. Our results show that even simple, generic High-throughput PBK modelling can provide accurate predictions of the pharmacokinetics of most compounds (87% of Cmax and 84% of AUC within 10-fold). Nevertheless, we also observe major differences in prediction accuracies between the different parameterisation strategies, as well as between different compounds. Finally, we outline a strategy for High-throughput PBK modelling that relies exclusively on freely available tools. Our findings contribute to a more robust understanding of the reliability of High-throughput PBK modelling, which is essential to establish the confidence necessary for its utilisation in Next-Generation Risk Assessment.

pharmacology and toxicology↗

bioRxiv2021

The NLRP3/eIF2 axis drives cell cycle progression in acute myeloid leukemia

Aberrant activation of the NLR family pyrin domain containing 3 (NLRP3) inflammasome mediates numerous inflammatory diseases. Oncogenes can activate the NLRP3 inflammasome and thereby promote myeloproliferative neoplasia, suggesting a crucial role of NLRP3 in the malignant transformation of hematopoietic cells. Here, we show that bone marrow-derived mononuclear cells of AML patients display enhanced expression of NLRP3, IL-1{beta} and IL-18 and that high-level expression of NLRP3 is linked to poor survival of AML patients. Pharmacological and genetic inhibition of NLRP3 inflammasome activation attenuated cell proliferation of MOLM-13 AML cells in vitro. In vivo, genetic inhibition of NLRP3 in MOLM-13 AML cells resulted in reduced engraftment potential in xenografts, along with reduced splenomegaly and organ infiltration. Differential proteomic analysis revealed the eIF2 pathway as potential target of NLRP3 in AML, with a significant increase of eIF2 phosphorylation upon NLRP3 inhibition. NLRP3 inhibition also caused a strong decrease in cyclin - dependent kinases CDK4 and CDK6, accompanied by an upregulation of the CDK inhibitor p21 (CDKN1A) and a marked arrest of cell cycle progression in the G0/G1 phase, consistent with the role of eIF2 phosphorylation as negative cell cycle regulator. Taken together, we show that inhibition of the NLRP3 inflammasome reduces AML cell proliferation by promoting eIF2 phosphorylation, which in turn enhances the expression of cell cycle arrest genes such as p21. Thus, the study uncovers the NLRP3/eIF2 axis as new driver of AML proliferation and proposes a novel therapeutic treatment of AML by targeted inhibition of NLRP3 activation.

immunology↗

bioRxiv2020

Laser-facilitated epicutaneous immunotherapy with hypoallergenic beta-glucan neoglycoconjugates suppresses lung inflammation and avoids local side effects in a mouse model of allergic asthma

BackgroundAllergen-specific immunotherapy via the skin targets an area rich in antigen presenting cells, but can be associated with local and systemic side effect. Allergen-polysaccharide neoglycogonjugates can increase immunization efficacy by targeting and activating dendritic cells via C-type lectin receptors and reduce side effects. ObjectiveWe investigated the immunogenicity, allergenicity and therapeutic efficacy of laminarin-ovalbumin neoglycoconjugates (LamOVA). MethodsThe biological activity of LamOVA was characterized in vitro using bone marrow derived dendritic cells. Immunogenicity and therapeutic efficacy was analyzed in BALB/c mice. Epicutaneous immunotherapy (EPIT) was performed using fractional infrared laser ablation to generate micropores in the skin and the effects of LamOVA on blocking IgG, IgE, cellular composition of BAL, lung, and spleen, lung function, and T cell polarization was assessed. ResultsConjugation of laminarin to ovalbumin reduced its IgE binding capacity 5-fold and increased its immunogenitiy 3-fold in terms of IgG generation. EPIT with LamOVA induced significantly higher IgG levels than OVA, matching the levels induced by s.c. injection of OVA/alum (SCIT). EPIT was equally effective as SCIT in terms of blocking IgG induction and suppression of lung inflammation and airway hyperresponsiveness, but SCIT was associated with a higher level of therapy induced IgE and TH2 cytokines. EPIT with LamOVA induced significantly lower local skin reactions during therapy compared to unconjugated OVA. ConclusionConjugation of the allergen to laminarin increased its immunogenicity while at the same time reducing local side effects. LamOVA EPIT via laser generated micropores is safe and equally effective to SCIT with alum, without the need for adjuvant.

immunology↗

bioRxiv2019

Ephrin receptor A4 (EphA4) is a new Kaposi’s sarcoma-associated herpesvirus virus entry receptor

Kaposis sarcoma-associated herpesvirus (KSHV) is a human {gamma}-herpesvirus associated with the development of Kaposis sarcoma (KS). KSHV target cells include endothelial cells, B cells, monocytes, epithelial cells, dendritic cells, macrophages, and fibroblasts. KSHV entry into target cells is a complex multistep process and is initiated by the binding and interaction of viral envelope glycoproteins with the cellular receptors. In our current studies, we have found that EphA4 promotes KSHV gH/gL-mediated fusion and infection better than EphA2 in HEK293T cells indicating that EphA4 is a new KSHV entry receptor. To confirm that epithelial cells express EphA2 and EphA4, we analyzed the expression of EphA2 and EphA4 in epithelial cells, endothelial cells, B cells, monocytes, fibroblasts using RNA-seq data analysis of existing data sets. We found these cell types broadly express both EphA2 and EphA4 with the exception of monocytes and B cells. To confirm EphA4 is important for KSHV fusion and infection, we generated EphA2 and EphA4 single and double knockout cells. We found that both EphA2 and EphA4 play a role in KSHV fusion and infection, since EphA2/EphA4 double knockout cells had the greatest decrease in fusion activity and infection compared to single knockout cells. Fusion and infection of KSHV was rescued in the EphA2/EphA4 double knock cells upon overexpression of EphA2 and/or EphA4. EphA2 binds to both EBV and KSHV gH/gL; however, EphA4 binds only to KSHV gH/gL. Taken together, our results identify EphA4 as a new entry receptor for KSHV.\n\nImportanceThe overall entry mechanism for herpesviruses is not completely known including that for the human {gamma}-herpesviruses Kaposis sarcoma-associated herpesvirus (KSHV) and Epstein-Barr virus (EBV). To fully understand the herpesvirus entry process, functional receptors need to be identified. In our current study, we found that EphA4 can also function for a KSHV entry receptor along with EphA2. Interestingly, we found that EphA4 does not function as an entry receptor for EBV whereas EphA2 does. The discovery of EphA4 as KSHV entry receptor has important implications for KSHV pathogenesis in humans and may prove useful in understanding the unique pathogenesis of KSHV infection in humans and may uncover new potential targets that can be used for the development of novel interventional strategies.

microbiology↗