Biology subjects

Mayer, J. U.

Publications and source records attributed to Mayer, J. U..

12 recordsLinked to original sources

bioRxiv2026

In vitro effects of tensile strain on cancer-associated and matched normal fibroblasts derived from oral squamous cell carcinoma: an exploratory study

BackgroundMechanical forces, particularly tensile stress, influence tumor progression by modulating cancer-associated fibroblast (CAF) behaviour and extracellular matrix remodelling, yet their role in oral cancer remains insufficiently defined. To our knowledge, this is the first study investigating in vitro tensile stress responses in CAF and normal fibroblasts (NF) derived from oral squamous cell carcinoma (OSCC). ObjectiveTo assess how tensile stress affects fibroblast gap closure, proliferation, metabolic activity, and paracrine signalling relevant to tumor-stroma interactions. MethodsCAFs and NFs were isolated from OSCC tissue and matched healthy mucosa and exposed to cyclic tensile strain (3%, 0.02 Hz, 96 h) using the FX-6000T system. Gap closure was assessed by wound-healing assay, proliferation by cell counting, metabolic activity by AlamarBlue, and paracrine effects on A549 tumor cell gap closure using fibroblast-conditioned supernatants. ResultsTensile loading significantly increased CAF gap closure capacity compared with both stimulated NFs (p<0.0001) and unstimulated CAF controls (p=0.0167). Metabolic activity showed a non-significant trend toward higher values in CAFs. Proliferation did not differ between groups up to 48 h, arguing against a major early contribution of proliferation to the observed group differences in the fibroblast scratch assays; however, because proliferation was not inhibited and was not quantified beyond 48 h, later time points should be interpreted conservatively as composite gap closure. Supernatants from mechanically stimulated CAFs increased A549 gap closure by [~]40% compared with non-stimulated controls (p=0.0485), whereas stimulated NFs did not enhance the tumor cells capacity to close the cell-free gap. ConclusionsTensile strain was associated with increased fibroblast gap closure and enhanced gap-closure-promoting paracrine effects of oral CAFs under the conditions tested. These exploratory findings support the concept that biomechanical cues can modulate CAF functional behaviour in OSCC. Given the limited cohort size and inter-patient variability, these results should be interpreted as hypothesis-generating and require confirmation in larger studies. Mechanistic pathways were not interrogated in this study and should be addressed in future work using more complex tumor-stroma models. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=127 SRC="FIGDIR/small/737904v1_ufig1.gif" ALT="Figure 1"> View larger version (46K): org.highwire.dtl.DTLVardef@d275c6org.highwire.dtl.DTLVardef@13249c5org.highwire.dtl.DTLVardef@8964b9org.highwire.dtl.DTLVardef@33e767_HPS_FORMAT_FIGEXP M_FIG C_FIG

biophysics↗

bioRxiv2026

Age-driven Dysregulation of murine Dendritic Cells is controlled by cell-intrinsic and extrinsic effects

Aging is associated with chronic, low-grade inflammation and progressive immune dysfunction. However, the current understanding of age-associated changes in dendritic cells across tissues is scarce. Studies exploring ageing-associated changes in dendritic cells (DCs) have reported either a general decline in the overall DC compartment or subset-specific alterations affecting cDC1, cDC2, and pDC populations across spleen, lung and liver, underscoring the considerable inconsistencies across tissues and studies. To underpin whether age-associated changes are extrinsic or intrinsic we investigated DCs across bone marrow, six peripheral tissues and in in vitro bone marrow derived DC cultures to examine the effects of aging on DC-poiesis, tissue distribution, and cellular states related to DC functionality and activation. We discovered that aging selectively alters DC development in the bone marrow by reducing cDC progenitor populations while preserving pDC-poiesis. In peripheral tissues, however, age-associated changes in DC homeostasis were strongly tissue-dependent. The most significant shifts in cDC1 and cDC2 frequencies occurred in barrier tissues, such as the lung and small intestine. In contrast, the spleen and liver exhibited more limited or variable changes. These quantitative alterations were accompanied by tissue-specific changes in phenotypic and activation-associated markers, including CD24, CD103, CD11b, MHCII, and CD86. Single-cell transcriptomic analyses of senescent p21-expressing DC across tissues and subsets indicated localized inflammatory states that aligned with local macrophage populations, pointing toward cell-extrinsic niches that contribute to local age-associated dysfunction. Notably, aged bone marrow retained the capacity to efficiently generate DCs in in vitro Flt3L cultures, and antigen-presenting function of BMDC to CD4 and CD8 T cells was maintained, pointing towards preserved cell-intrinsic functions, albeit subset-specific differences in activation and inhibitory receptor expression in response to different pattern-recognition receptor agonists. Collectively, our findings indicate that aging does not superimpose a uniform alteration module to the DC compartment across tissues, but instead promotes selective alterations in DC ontogeny and tissue-specific remodeling of DC phenotypes and cellular states.

immunology↗

bioRxiv2026

Cross-Domain Transfer Learning from Peptides to Lipids Using a Multi-Property Fine-Tuned LLM

Accurate knowledge of liquid chromatography retention time (RT) is essential for confident compound identification in metabolomics and lipidomics. Yet, it is often constrained by the scarcity of experimental data for many molecular classes. Current workflows depend on experimental RT libraries, which are time-consuming to build and limited to previously observed compounds. Here, we present a transfer learning pipeline that leverages large, publicly available peptide datasets to enable accurate lipid RT prediction in data-sparse scenarios. We first show that a ChemBERTa language model, when pre-trained on peptides with a multi-task objective (predicting both RT and fundamental RDKit molecular descriptors), learns a more robust and generalizable chemical representation than a single-task (RT-only) model. This multi-property pre-training yielded superior generalization in lipids, achieving test R2 values of 0.842 against 0.814 (RT-only). Crucially, transferring this peptide-based model to lipid data provided a pronounced advantage in data-sparse scenarios. When fine-tuned on only 5% of available lipid data, the transferred model improved the median test R2 by +0.234 over a model trained from scratch. Significant benefits persisted at intermediate data scales (50-75%), with performance converging only when 100% of the lipid data was used. Notably, the pre-trained model never underperformed the baseline, exhibiting more stable training across all data scales. These results demonstrate that multi-property pre-training guides language models towards chemically meaningful representations that support better RT prediction in different molecular domains. Furthermore, peptide-based pre-training facilitates cross-domain transfer of chemical properties to lipid. Our work provides a practical, scalable strategy to mitigate data scarcity in lipidomics by transferring knowledge from data-rich peptide databases, offering a computational alternative to extensive experimental library generation and enabling more confident identification in small-scale omics studies.

bioinformatics↗

bioRxiv2025

KDM6B inhibition modulates monocyte activation and alleviates IMQ-psoriasis skin inflammation

Inflammatory monocytes are increasingly recognized as key amplifiers of psoriasis, yet the epigenetic drivers of their pathogenic signature remain unclear. Here, we demonstrate that the histone demethylase KDM6B is markedly upregulated and catalytically active in classical monocytes during the imiquimod (IMQ)-induced psoriasis model. This is associated with reduced levels of the repressive histone mark H3K27me3, an epigenetic modification linked to chromatin compaction and transcriptional silencing, at the Il1b, Tnf, Pgam1, Pgk1, and Aldoa promoters, together with an enhanced inflammatory and glycolytic gene signature. Pharmacological blockade of KDM6B after disease onset using GSK-J4, a cell-permeable prodrug that is intracellularly converted to the active KDM6B inhibitor GSK-J1, restores H3K27me3 at inflammatory and metabolic loci, suppresses Il1b/Tnf transcription, normalizes bioenergetic profiles, and reduces monocyte and neutrophil recruitment to the inflamed skin. Single-cell transcriptomic profiling further reveals that KDM6B inhibition represses cytokine-mediated signaling, glycolysis, and chemotaxis pathways in monocytes, yet enriches antigen presentation modules, consistent with a shift toward a homeostatic, antigen-presenting surveillance program in myeloid cells and a Treg-supportive milieu. Collectively, our data identify KDM6B as an epigenetic-metabolic switch that sustains monocyte-driven inflammation in the IMQ-induced psoriasis model. Importantly, we provide preclinical evidence that targeting KDM6B can reduce maladaptive inflammatory response even in progressed diseases. These findings propose KDM6B inhibitors as a promising adjunct to current biologics for psoriasis and other myeloid-driven autoinflammatory disorders. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=178 HEIGHT=200 SRC="FIGDIR/small/682023v1_ufig1.gif" ALT="Figure 1"> View larger version (58K): org.highwire.dtl.DTLVardef@efef15org.highwire.dtl.DTLVardef@395983org.highwire.dtl.DTLVardef@123e832org.highwire.dtl.DTLVardef@615f84_HPS_FORMAT_FIGEXP M_FIG C_FIG

immunology↗

bioRxiv2025

Depletion of CX3CR1+ macrophages results in disrupted functionality and immune surveillance within epididymis and testis

A finely tuned immune regulation within the epididymis and testis is essential for male reproductive health. This balance is especially critical in the epididymis, where sperm mature and ascending infections frequently disrupt homeostasis, resulting in regionally different immune responses and potential long-term fertility impairments. We previously demonstrated that the epididymis harbors a region-specific immunological scaffold, with CX3CR1+ macrophages as the most prominent epithelium-associated immune cell population. Here, we established a transgenic mouse model to selectively deplete these intraepithelial CX3CR1+ macrophages within the epididymis, resulting in focal epithelial damage and impaired sperm maturation processes essential for proper sperm functionality. Additionally, a mild reduction of the testicular macrophage pool resulted in transient disruptions in spermatogenesis and steroidogenesis. Although the macrophage niche was repopulated after depletion, the newly recruited cells displayed altered phenotypes consistent with persistent sperm alterations. Following infection with uropathogenic Escherichia coli (UPEC), macrophage-depleted mice exhibited exacerbated immune responses - particularly in normally protected proximal epididymal regions - with earlier onset and more severe tissue damage. Transcriptomic analysis revealed a failure to restrain inflammatory responses, especially in genes involved in immune regulation and antibacterial defense, accompanied by elevated immune cell infiltration in infected macrophage-depleted mice. Overall, our findings confirm a crucial role for CX3CR1 macrophages in preserving epithelial integrity and modulating immune responses, supporting a stable tissue environment necessary for efficient organ function of both epididymis and testis. Significance statementMaintaining immune balance in the epididymis is essential for tissue health and protection against ascending infections. Using a transgenic mouse model that allows for selective depletion of CX3CR1 macrophages, this study examines their role in both the epididymis and testis under normal and infectious conditions. The results show that the removal of these macrophages causes localized epithelial damage, changes in immune cell make-up, and increased inflammation in the epididymis after bacterial infection, while also causing mild, reversible problems with spermatogenesis and steroid production in the testis. These findings support the idea that CX3CR1 macrophages contribute to region-specific immune regulation and epithelial stability--key features for keeping the tissue environment suitable for proper sperm development.

immunology↗

bioRxiv2025

The quest continues: Human CD4+ CD16+ CD56+ "exTreg" resemble NKT cells instead

Regulatory T cells are essential for immune tolerance, but their loss of function under inflammatory conditions in murine models signify a risk factor for Treg-based therapies. Recently CD4+ CD56+ CD16+ T cells were suggested to resemble such ex-Treg in human PBMC. Here, we re-evaluate the identity of the CD4+ CD56+ CD16+ population at a phenotypic and transcriptomic level using multiparametric flow cytometry on human PBMC and CITE-seq analysis to demonstrate that the CD4+ CD56+ CD16+ cells mostly constitute NKT cells instead. Further, we evaluated the stability of human Treg under lineage-challenging conditions and observe robust lineage stability in vitro. Finally, we also explore the potential of Tr17 induction using TGF-{beta} and IL-6, a possible therapeutic strategy for Treg ex vivo expansion-based therapies. Together, we conclude that human exTreg remain to be described and instead human Treg present as remarkably stable, further promoting Treg-based adoptive transfer therapies.

immunology↗

bioRxiv2025

Integrating the ENCODE blocklist for machine learning quality control of ChIP-seq with seqQscorer

MotivationQuality assessment of next-generation sequencing data is a complex but important task to ensure correct conclusions from experiments in molecular biology, biomedicine, and biotechnology. We previously introduced seqQscorer, a quality assessment tool using machine learning to support this process. To improve seqQscorer in terms of accuracy and processing time, we integrated the ENCODE blocklist* to derive a new type of quality-related features, supposed to be more informative and faster in generation than those conventionally used by seqQscorer. ResultsThe novel seqQscorer extension, called seqBLQ, allows us to improve the quality assessment for ChIP-seq data derived from human tissues and cell lines. Furthermore, seqBLQ enhances the usability of the tool by simplifying the installation procedure and reducing the computational resources required for feature generation. Availability and implementationhttps://github.com/salbrec/seqQscorer

bioinformatics↗

bioRxiv2022

The regional distribution of resident immune cells shapes distinct immunological environments along the murine epididymis

Summary/ AbstractThe epididymis constitutes an important transition zone for post-testicular sperm maturation and storage. As the organ consists of a single convoluted duct, inflammation-associated tissue damage has a severe impact on fertility. In order to clarify the reasons for region-specific differences in the intensity of immune responses observed in a mouse model of acute bacterial epididymitis, we investigated the heterogeneity of resident immune cell populations within the epididymis under physiological conditions by scRNASeq analysis of extravascular CD45+ cells. 12 distinct immune cell subsets were identified, displaying substantial differences in distribution along the epididymis. Several distinct subsets of macrophages constituted the majority of these cells. Crucially, the proximal and distal regions showed striking differences in their immunological landscapes. These findings indicate that resident immune cells are strategically positioned along the epididymal duct, potentially providing different immunological environments required for sperm maturations and elimination of pathogens ascending the urogenital tract.

immunology↗

bioRxiv2021

The skin environment controls local dendritic cell differentiation and function through innate IL-13

The signals driving the adaptation of type-2 dendritic cells (DC2s) to diverse peripheral environments are not well understood. We show that the development of CD11blow migratory DC2s, a DC2 population unique to the dermis, requires STAT6- and KLF4-dependent IL-13 signaling, whereas DC2s in lung and small intestine are STAT6-independent. Dermal IL-13 is mostly derived from innate lymphoid cells expressing a resting ICOS+ KLRG1-ST2-phenotype. Analysis of public datasets indicates that human skin DC2s also express an IL-4/IL-13 gene signature compared to blood or spleen, suggesting a similar developmental pathway in mice and humans. In the absence of IL-13 signaling, dermal DC2s are stable in number but remain CD11bhi and show defective activation in response to allergen with diminished ability to support IL-4+ GATA3+ Th development, whereas anti-fungal IL-17+ ROR{gamma}t+ responses are increased. Thus, steady-state IL-13 fosters a non-inflammatory and pro-allergic environment in healthy skin via conditioning of local DC2s.

immunology↗

bioRxiv2020

Fate mapping analysis reveals a novel dermal migratory Langerhans-like cell population

Dendritic cells residing in the skin represent a large family of antigen presenting cells, ranging from long-lived Langerhans cells (LC) in the epidermis to various distinct classical dendritic cell subsets in the dermis. Through genetic fate mapping analysis and single cell RNA sequencing we have identified a novel separate population of LC-independent CD207+CD326+ LClike cells in the dermis that homed at a slow rate to the LNs. These LClike cells were long-lived and radioresistant but, unlike LCs, they were gradually replenished by bone-marrow-derived precursors under steady state. LClike cells together with cDC1s were the main migratory CD207+CD326+ cell fractions present in the LN and not, as currently assumed, LCs, which were barely detectable, if at all. These findings bring new insights into the dynamism of cutaneous dendritic cells and opens novel avenues in the development of treatments to cure inflammatory skin disorders.

immunology↗

bioRxiv2019

Design and Optimization Protocol for High-Dimensional Immunophenotyping Assays using Spectral Flow Cytometry

Technological advances in fluorescence flow cytometry and an ever-expanding understanding of the complexity of the immune system has led to the development of large 20+ flow cytometry panels. Yet, as panel complexity and size increases, so does the difficulty involved in designing a high-quality panel, accessing the instrumentation capable of accommodating large numbers of parameters, and in analysing such high-dimensional data.\n\nA recent advancement is spectral flow cytometry, which in contrast to conventional flow cytometry distinguishes the full emission spectrum of each fluorochrome across all lasers, rather than identifying only the peak of emission. Fluorochromes with a similar emission maximum but distinct off-peak signatures can therefore be accommodated within the same flow cytometry panel, allowing greater flexibility in terms of panel design and fluorophore detection.\n\nHere, we highlight the specific characteristics regarding spectral flow cytometry and aim to guide users through the process of building, designing and optimising high-dimensional spectral flow cytometry panels using a comprehensive step-by-step protocol. Special considerations are also given for using highly-overlapping dyes and a logical selection process an optimal marker-fluorophore assignment is provided.

immunology↗

bioRxiv2019

Single-cell analysis of intestinal immune cells during helminth infection

Single cell isolation from helminth infected intestines has been notoriously difficult, due to the strong anti-parasite type 2 immune responses that drive mucus production, tissue remodeling and immune cell infiltration. Through the systematic optimization of a standard intestinal digestion protocol, we were able to isolate millions of immune cells from heavily infected tissues. Using this protocol, we validated many hallmarks of anti-parasite immunity and analyzed immune cells from the lamina propria and granulomas during helminth development, as well as acute and chronic worm infection.

immunology↗